CN114599653A - Indazoles as hematopoietic progenitor kinase 1 (HPK1) inhibitors and methods of use - Google Patents

Abstract

The present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, compositions containing the compounds, methods of using the compounds to treat various diseases associated with HPK1, and methods of making these compounds.

Description

Indazoles as hematopoietic progenitor kinase 1 (HPK1) inhibitors and methods of use

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to US Provisional Patent Application No. 63/084,059, filed on September 28, 2020. The entire disclosure of this application identified in this paragraph is incorporated herein by reference.

technical field

The present disclosure relates to inhibitors of hematopoietic progenitor kinase 1 (HPK1), pharmaceutical compositions containing the inhibitors, methods of using the inhibitors to treat various diseases associated with HPK1, and methods of making these compounds.

Background technique

Immunotherapy is a type of treatment that uses the body's own immune system to help fight cancer and other diseases. In recent years, this relatively new approach has achieved remarkable clinical success in the treatment of multiple tumor types, especially in the treatment of immune checkpoint inhibitors and chimeric antigen T-cell therapy. The most studied checkpoint inhibitors include CTLA4, PD-1, or PD-L1 inhibitors, which have shown significant antitumor activity by overcoming immunosuppressive mechanisms at the tumor site.

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a serine/threonine kinase that is a member of MAP4K. HPK1 is significantly expressed in a subset of hematopoietic cell lineages. HPK1 is a newly discovered key negative regulator in T lymphocyte and dendritic cell activation. The important role of the kinase activity of HPK1 as a novel intracellular checkpoint molecule in anticancer immunity has recently been demonstrated, as well as the potential advantages of combination therapy with existing checkpoint regimens. HPK1 inhibition is expected to have a dual function, 1. prolonging T cell activation and 2. enhancing APC function through dendritic cells. This dual targeting may work synergistically for an effective immune response in the tumor microenvironment. Therefore, HPK1 has been confirmed as a new target for anticancer immunotherapy. Examples of cancers treated using the compounds of the present disclosure include, but are not limited to, epithelial cancer, melanoma, blastoma, sarcoma, lymphoma, and all forms of leukemia, including but not limited to bladder cancer, brain tumor, breast cancer, cervical cancer, Colorectal, esophageal, endometrial, hepatocellular, laryngeal, lung, osteosarcoma, ovarian, pancreatic, prostate, renal and thyroid cancers, acute lymphoblastic leukemia, acute myeloid leukemia, ventricular Ewen's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma, and Wilms tumor (Wilm's tumor).

Inhibition of HPK1 with small molecule inhibitors has the potential to treat cancer and other diseases [Hernandez, S., et.al., (2018) Cell Reports 25, 80-94].

SUMMARY OF THE INVENTION

The present disclosure provides novel indazole compounds and pharmaceutically acceptable salts that are potent HPK1 inhibitors and dual activators of T cells and dendritic cells.

One embodiment of the present invention is a compound of formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Het, M and L are as defined in the specific embodiments.

In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In yet another embodiment, there is provided a method of treating a subject having a disease or disorder associated with HPK1 modulation, comprising: administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable amount thereof Accepted salt.

Detailed ways

The following description is merely exemplary in nature and is not intended to limit the disclosure, application, or uses.

definition

For clarity, generic terms used in this disclosure are defined herein.

This specification uses the terms "substituent", "radical", "group", "moiety" and "fragment" interchangeably.

As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group having at least one site of unsaturation, ie, a carbon-carbon sp2 double bond. In one embodiment, the alkenyl group has 2-12 carbon atoms. In some embodiments, the alkenyl group is a C2 _{- C10} alkenyl group or a C2 _{- C6} alkenyl group. Examples of alkenyl groups include, but are not limited to, ethylene or vinyl (—CH═CH ₂ ), allyl (—CH ₂ CH═CH ₂ ), cyclopentenyl (—C ₅ H ₇ ), and 5-hexenyl _{( —CH2CH2CH2CH2CH═CH2 ) . _}

As used herein, the term "alkoxy" is RO—, where R is an alkyl group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and propoxy.

As used herein, the term "alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, and ethoxyethyl.

As used herein, the term "alkoxycarbonyl" is ROC(O)—, where R is an alkyl group as defined herein. In various embodiments, R is C ₁ -C ₁₀ alkyl or C ₁ -C ₆ alkyl.

As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group. In one embodiment, the alkyl group has 1-12 carbon atoms. In some embodiments, the alkyl group is a C ₁ -C ₁₀ alkyl group or a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" refers to an alkyl group having 1-4 carbon atoms.

As used herein, if the term " _C1 - _C6 " is used, it means that the number of carbon atoms is 1-6. For example, a C ₁ -C ₆ alkyl group refers to an alkyl group having any integer of 1-6 carbon atoms.

As used herein, the term "alkylamino" refers to an amino group substituted with one or more alkyl groups. "N-(alkyl)amino" is _RNH- and "N,N-(alkyl)2amino" is _R2N- , wherein the R groups are alkyl as defined herein and are the same or different. In various embodiments, R is C ₁ -C ₁₀ alkyl or C ₁ -C ₆ alkyl. Examples of alkylamino groups include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and methylethylamino.

As used herein, the term "alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, wherein alkylamino is as defined herein. Examples of alkylaminoalkyl include methylaminomethyl and ethylaminomethyl.

As used herein, the term "alkynyl" refers to a straight or branched carbon chain group having at least one site of unsaturation, ie, a carbon-carbon sp triple bond. In one embodiment, the alkynyl group has 2-12 carbon atoms. In some embodiments, the alkynyl group is a C2 _{- C10} alkynyl group or a C2 _{- C6} alkynyl group. Examples of alkynyl groups include alkynyl (—C≡CH) and propargyl ( _—CH2C≡CH ).

As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic or includes a carbon fused to a 5 or 6 membered cycloalkyl group Aromatic ring system of 5-14 carbon atoms of a cyclic aromatic group. Representative examples of aryl groups include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and indanyl. Carbocyclic aryl groups can be unsubstituted or optionally substituted.

As used herein, the term "cycloalkyl" is a hydrocarbyl group containing at least one saturated or partially unsaturated ring structure and attached through a ring carbon. In various embodiments, it refers to a saturated or partially unsaturated C3 _- C12 cyclic moiety, examples _of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexyl Hexenyl, cycloheptyl and cyclooctyl. "Cycloalkoxy" is RO—, where R is cycloalkyl.

As used herein, the terms "halogen" and "halo" refer to chlorine (—Cl), bromine (—Br), fluorine (—F), or iodine (—I). " _Haloalkoxy " refers to an alkoxy group substituted with one or more halo groups, examples of haloalkoxy include, but are not limited to, _—OCF3 , _—OCHF2 , and —OCH2F. "Haloalkoxyalkyl" refers to an alkyl moiety substituted with a haloalkoxy, wherein haloalkoxy is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl, and trifluoromethoxyethyl. "Haloalkyl" refers to an alkyl moiety substituted with one or more halo groups. Examples of haloalkyl include _-CF3 and _-CHF2 .

As used herein, the term "heteroalkyl" refers to a straight or branched chain alkyl group having 2-14 carbons (in some embodiments, 2-10 carbons) in the chain, one or more of which have been heteroalkyl Atom substitution, heteroatoms are selected from S, O, P and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.

As used herein, the term "heterocyclyl" includes heteroaryl groups as defined below, and refers to saturated or partially unsaturated groups having 2-14 ring carbon atoms and 1-4 heteroatoms in addition to the ring carbon atoms The monocyclic, bicyclic or tricyclic group of the heteroatom is selected from P, N, O and S. In various embodiments, a heterocyclic group is attached to another moiety through a carbon or through a heteroatom, and is optionally substituted on the carbon or heteroatom. Examples of heterocyclyl groups include azetidinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzopyrazolyl, benzotriazolyl, benzothiophene, benzoxyl azolyl, carbazolyl, carboline, cinnamyl, furanyl, imidazolyl, indoline, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, Isoquinolinyl, isothiazolyl, isoxazolyl, naphthidyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyran base, tetrahydroisoquinolinyl, tetrazolyl, tetrazolium pyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexa Hydroazepinyl, piperazinyl, piperidinyl, pyridin-2-one, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydro Benzophenylthio, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, indoline, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, Dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazole base, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothienyl, and N-oxides thereof . "Heterocyclyloxy" is RO—, where R is heterocyclyl. "Heterocyclylthio" is RS—, where R is heterocyclyl.

As used herein, the term "3- or 4-membered heterocyclyl" refers to a monocyclic ring having 3 or 4 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of N, O, and S. Non-limiting examples of 3- or 4-membered heterocyclyl groups include aziridinyl, 2H-aziridinyl, oxiranyl, thiirane, azetidinyl, 2,3- Dihydroazetadienyl, azetadienyl, 1,3-diazetidine, oxetanyl, 2H-oxetanyl, thietanyl and 2H -Thia group.

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 in the ring A heteroatom selected from the group consisting of N, O, and S. Non-limiting examples of heteroaryl groups include pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxalyl azolyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzofuranyl, dibenzofuranyl, dibenzothiophene, benzothienyl, indolyl, Benzothiazolyl, benzoxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thienyl and pyrazinyl. The attachment of the heteroaryl group can occur through an aromatic ring, or, if the heteroaryl group is bicyclic or tricyclic and one of the rings is not aromatic or contains no heteroatoms, then through a non-aromatic or heteroatom free ring. "Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. "Heteroaryloxy" is RO—, where R is heteroaryl.

As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with hydroxy (-OH), wherein alkoxy is as defined herein. An example of hydroxyalkoxy is hydroxyethoxy.

As used herein, the term "hydroxyalkyl" refers to a straight or branched chain monovalent _C1 - _C10 hydrocarbon group substituted with at least one hydroxy group, and examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxy propyl and hydroxybutyl.

As used herein, the term "pharmaceutically acceptable" means suitable for use in pharmaceutical formulations, generally recognized as safe for such use, duly approved for such use by a regulatory agency of a national or state government, or listed in the United States Pharmacopeia or other recognized pharmacopoeia for animals, especially humans.

As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier, or other ingredient that is pharmaceutically acceptable and that is administered with a compound of the present invention.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that enhances the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts, metal salts and amine salts with inorganic or organic acids. Examples of acid addition salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Examples of acid addition salts formed with organic acids such as acetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, Maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane Disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2 -ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis(3-hydroxy-2-naphthylmethyl) acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid , lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. Examples of metal salts include salts formed with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogenous bases that are strong enough to form salts with carboxylic acids.

As used herein, the term "substituted" refers to any of the foregoing groups (ie, alkyl, aryl, heteroaryl, heterocycle, or cycloalkyl) wherein at least one hydrogen atom of the substituted moiety is replaced with a substituent . In one embodiment, each carbon atom of the substituted group is substituted with no more than two substituents. In another embodiment, each carbon atom of the substituted group is substituted with no more than one substituent. In the case of a ketone substituent, the two hydrogen atoms are replaced by oxygen attached to the carbon through a double bond. Unless otherwise defined, substituents include halogen, hydroxy, (lower)alkyl, haloalkyl, mono- or dialkylamino, aryl, heterocycle, -NO ₂ , B(OH) ₂ , BPin, -NR _a R _b , -NR _a C(=O)R _b , -NR _a C(=O)NR _a R _b , -NR _a C(=O) OR _b , -NR _a SO ₂ R _b , -OR _a , -CN , -C(=O)R _a , -C(=O)OR _a , -C(=O)NR _a R _b , -OC(=O)R _a , -OC(=O)OR _a , -OC (=O)NR _a R _b , -NR _a SO ₂ R _b , -PO ₃ R _a , -PO(OR _a )(OR _b ), -SO ₂ R _a , -S(O)R _a , -SO (N)R _a (eg, sulfoximine), -(R _a )S=NR _b (eg, sulfimide), and -SR _a , where _Ra and R _b are the same or different, and are independently -H, halogen, amino, alkyl, haloalkyl, aryl or heterocycle, or wherein _Ra and _Rb together with the nitrogen atom to which they are attached form a heterocycle. _Ra and _Rb can be plural based on the atoms to which they are attached.

As used herein, the term "therapeutically effective amount" means when applied to a compound of the present invention, is intended to mean sufficient to ameliorate, alleviate, stabilize, reverse, slow or delay disease progression or disease state, or symptoms of a disorder or disease. In one embodiment, the methods of the present invention provide for administration of a combination of compounds. In this context, a "therapeutically effective amount" is an amount of a compound of the invention in combination sufficient to cause the desired biological effect.

As used herein, the term "treatment" or "treating" as used herein refers to ameliorating or reversing the progression or severity of a disease or disorder, or ameliorating or reversing one or more of such a disease or disorder symptoms or side effects. As used herein, "treatment" or "treating" also refers to inhibiting or blocking the progression of a system, symptom or state of a disease or disorder, such as delaying, retarding, restraining, hindering or hindering. For the purposes of the present invention, "treatment" or "treating" further refers to a method of obtaining a beneficial or desired clinical outcome, wherein "beneficial or desired clinical outcome" includes, but is not limited to, reduction of symptoms , reduction in the extent of disease or disease, stabilization (ie, not worsening) of disease or disease state, delay or alleviation of disease or disease state, improvement or alleviation of disease or disease state, and alleviation of disease or disease state, in part or in whole.

compound

The present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

X is O or S;

L is a bond, -O-, -S- or -NR ⁶ -;

R1 is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein R1 is optionally substituted with ^one or more substituents independently selected from ^{R7 ;}

R ⁶ is -H or C _1-6 alkyl;

R ⁷ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, oxo, cyano, hydroxyl, - C(O)R ⁹ , -C(O)OR ⁹ , -C(O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -SR ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N( R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ , -N(R ⁶ )C (O)NR ¹⁰ R ¹¹ , -N(R ⁶ )S(O) ₂ R ⁹ , -N(R ⁶ )S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ ;

R ⁹ is -H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

Each R ¹⁰ and R ¹¹ is independently -H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclic group optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, Haloalkyl, hydroxyalkyl, -CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(= O)OR ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(=O)R ⁹ , -OC( =O) OR ⁹ and the group consisting of -OC(=O)NR ¹⁰ R ¹¹ ;

Each of R ¹² and R ¹³ is independently C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, or R ¹² and R ¹³ Together with the phosphorus atom to which they are attached form a 4-8 membered heterocyclic group optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkane base, -CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)OR ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(=O)R ⁹ , -OC(=O)OR ⁹ and the group consisting of -OC(=O)NR ¹⁰ R ¹¹ ;

Het is selected from the group consisting of:

R ^a , R ^b and R ^c are each independently -H, -D, halogen, -CF ₃ , -CF ₂ H, -CH ₂ F, -CN, -OR ⁹ or -NR ¹⁰ R ¹¹ ;

R ² is -H, -D, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen , hydroxyl, -CD ₂ OH, -CN, -NO ₂ , haloalkyl, trimethylsilylethoxymethyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O )NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -SR ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , - S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N (R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ , -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ , -N(R ⁶ )S(O) ₂ R ⁹ , -N(R ⁶ )S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ , wherein C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, alkane group, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)OR ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(= ^The group consisting of O) ^R9 , -OC(=O) ^OR9 and -OC(=O) ^NR10R11 ;

R ³ is -H, -D, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen substituted, cyano, hydroxyl, -CH ₂ OH, -CD ₂ OH, -OH, -CN, -NO ₂ , haloalkyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O )NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -SR ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , - S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N (R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ , -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ , -N(R ⁶ )S(O) ₂ R ⁹ , -N(R ⁶ )S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ ;

M is a bond, -O-, -S- or -NR ⁶ -;

R ⁶ is -H or C _1-6 alkyl;

R ⁴ is -H, -D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, Hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O)NR ¹⁰ R ¹¹ , -S(O) ₂ R ⁹ , -S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ , wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl , heteroaryl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD ₃ , -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)OR ⁹ , -NR ¹⁰ S (O) ₂ R ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(=O)R ⁹ , - the group consisting of OC(=O) ^OR9 and -OC(=O) ^{NR10R11 ;} and

R ⁵ is -H, -D, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, hydroxyl, -CH ₂ OH, -CD ₂ OH, -CN or haloalkyl.

In some embodiments, L is a bond, and R ¹ is a cycloalkyl group, optionally substituted with one or more groups selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC( O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N(R ⁶ )C(O ) R ⁹ , the group consisting of -N(R ⁶ )C(O)OR ⁹ and -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ .

In some embodiments, R ² and R ³ are each independently -H, halo, alkylthio, haloalkyl, or alkyl.

In some embodiments, M is a bond, -O- or -NR ⁶ -; and R ⁴ is -H, -D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O)NR ¹⁰ R ¹¹ , -S(O) ₂ R ⁹ , - S(O)(=NH)R ¹⁰ or -S(O) ₂ NR ¹⁰ R ¹¹ , wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl radical, heteroaryl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD _3. The group consisting of -NR ¹⁰ R ¹¹ , -NR ¹⁰ S(O) ₂ R ⁹ and -NR ¹⁰ C(=O)R ⁹ .

In another embodiment, compounds of formula (II) are provided:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ^Ra , R ^b , M and L are as defined in formula (I) above.

In some embodiments, L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C _1-3 alkyl, C _1-3 hydroxyalkyl and C _1-3 haloalkyl groups; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkyl or halogen; M is a bond, -O-, -S -or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propyl amidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkane Oxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methyl sulfide Methyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl ^; and R5 is -H, alkyl or halogen. Non-limiting exemplary compounds of formula (II) include Examples 1 and 2 of Table 1 .

In another embodiment, compounds of formula (III) are provided:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ^Ra , R ^b , M and L are as defined in formula (I) above.

In some embodiments, L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C _1-3 alkyl, C _1-3 hydroxyalkyl and C _1-3 haloalkyl groups; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkyl or halogen; M is a bond, -O-, -S -or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl, propyl amidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl, alkane Oxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl, methyl sulfide Methyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1,3,3,3-d6)amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl ^; and R5 is -H, alkyl or halogen. Non-limiting exemplary compounds of formula (III) include Examples 3 and 23 of Table 1 .

In another embodiment, compounds of formula (IV) are provided:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ^Ra , R ^b , M and L are as defined in formula (I) above. Non-limiting exemplary compounds of formula (IV) include Examples 24 and 307 of Table 1 .

In some embodiments, L is a bond, and R ¹ is a cycloalkyl group, optionally substituted with one or more groups selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC( O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N(R ⁶ )C(O ) R ⁹ , the group consisting of -N(R ⁶ )C(O)OR ⁹ and -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ .

In some embodiments, L is a bond; R is cycloalkyl, optionally substituted with ^one or more groups selected from halogen, C _1-3 alkyl, C _1-3 hydroxyalkyl, and The group consisting of C _1-3 haloalkyl groups. In certain embodiments, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl.

In some embodiments, L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxy The group consisting of alkyl and C ₁ -C ₃ haloalkyl; R ² is -H, alkyl, haloalkyl or halogen; R ³ is -H, alkyl or halogen; M is bond, -O- or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, monoalkylamino or dialkylamino; R ⁵ is -H, alkyl or halogen. In particular embodiments, L is a bond; R ^a is -H; R ^b is -H; R ¹ is chloro, fluoro, C ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, or C ₁ - C ₃ haloalkyl substituted cyclopropyl; R ² is -H, alkyl, chlorine or fluorine; R ³ is -H, alkyl, chlorine or fluorine; M is a bond or -NH-; R ⁴ is -H, chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, methylamino or dimethylamino ^; and R5 is -H or alkyl. In certain embodiments, L is a bond; R ^a is -H; R ^b is -H; R ¹ is cyclopropyl substituted with chlorine or fluorine; R ² is -H, chlorine or fluorine; R ³ is -H , chlorine or fluorine; M is a bond or -NH- ^; R4 is -H, chlorine, fluorine, methyl, ethyl, propyl or isopropyl ^; and R5 is -H. Non-limiting exemplary compounds having such substituents include Examples 61, 64, 84, 85, 86, 155, 156, and 157 of Table 1 .

In some embodiments, L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxy The group consisting of alkyl and C ₁ -C ₃ haloalkyl; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkyl or halogen; M is a bond, -O- , -S- or ^{-NR6- ;} R4 is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, monoalkylamino or dialkylamino ^; and R5 is -H, alkyl or halogen. Non-limiting exemplary compounds having such substituents include Examples 33, 39, 40, 46, 82, 102, 141, 166, 228, and 286 of Table 1 .

In some embodiments, L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxy The group consisting of alkyl and C ₁ -C ₃ haloalkyl; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkyl or halogen; M is a bond, -O- , -S- or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, aminocarbonylalkyl, acetamidoethyl , propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl(methoxy)methyl group, alkoxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl, trifluoroacetamidoethyl , methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1,3,3,3-d6 ) amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methylpyrazolylmethyl; and R ⁵ is -H, alkyl or halogen. Non-limiting exemplary compounds having such substituents include Examples 26, 27, 34, 38, 41-44, 50, 58, 62, 63, 66, 68, 73, 77, 79, 80, 83, 87, 88, 90-92, 94, 96, 101, 105, 107, 110, 113, 116, 118-120, 128, 130, 131, 133, 134, 136, 141, 153, 160, 162, 166-168, 170, 173-176, 179, 181, 183, 186, 188, 190, 191, 194, 208, 210, 213, 215-219, 221, 223, 226, 228, 232, 235, 237, 248, 250, 252, 257, 261, 262, 264, 266, 268, 269, 272, 273, 284-290, 295, 300 and 302-305.

In one embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Medical uses and methods of treatment using the compound

The present disclosure provides methods of treating a subject having a disease or disorder associated with HPK1 modulation, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof . In some embodiments, the disease or disorder associated with the regulation of HPK1 is cancer, metastasis, inflammation, or an immune disease including an autoimmune disease.

In some other embodiments, the disease is cancer, metastasis, inflammation, or an autoimmune disease. In specific embodiments, the cancer is selected from the group consisting of epithelial cancer, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including but not limited to bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, Esophageal, endometrial, hepatocellular, laryngeal, lung, osteosarcoma, ovarian, pancreatic, prostate, renal and thyroid cancers, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma, and Wilms tumor (Wilm's tumor).

In some embodiments, the autoimmune disease is inflammatory bowel disease, Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, hemolytic anemia, autoimmune hepatitis, Behcet's disease, Berger's disease, Bullous pemphigoid, cardiomyopathy, celiac disease, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, cold Aggregate disease, type 1 diabetes, discoid lupus, primary mixed cryoglobulinemia, Graves disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hypothyroidism, autoimmune lymphoid syndrome syndrome (ALPS), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), juvenile arthritis, lichen planus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, severe Myasthenia, pemphigus vulgaris, pernicious anemia, polychondritis, autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis, primary agammaglobulinemia, Primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff person syndrome disease, Takayasu arteritis, giant cell arteritis, ulcerative colitis, uveitis, vasculitis, or granulomatosis with polyangiitis.

In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting HPK1 activity in a subject in need of inhibition of HPK1 activity. In some embodiments, the use includes treating cancer or autoimmune disease.

Suitable subjects to be treated according to the present disclosure include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., and include mammals in utero. Subjects can be of any gender and at any stage of development. In one embodiment, a suitable subject to be treated according to the present disclosure is a human.

The compounds of the present disclosure are generally administered in a therapeutically effective amount. The compounds of the present disclosure may be administered by any suitable route in the form of pharmaceutical compositions suitable for such route and in dosages effective for the intended treatment. Effective doses are generally in the range of about 0.01 to about 1000 mg/kg body weight/day, preferably about 0.01 to about 500 mg/kg/day, in single or divided doses. Dosage levels below the lower end of this range may be appropriate depending on the age, species, and disease or condition being treated. In other cases, larger doses can be used without harmful side effects. The larger dose can also be divided into several smaller doses for administration throughout the day. Methods for determining appropriate dosages are well known in the art to which this disclosure pertains. For example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ^ed ., 2000 can be used.

Pharmaceutical Compositions, Dosage Forms and Routes of Administration

For the treatment of the above-mentioned diseases or conditions, the compounds described herein, or a pharmaceutically acceptable salt thereof, can be administered as follows:

Oral administration

The compounds of the present disclosure may be administered orally, including by swallowing, such that the compound enters the gastrointestinal tract, or is absorbed directly from the oral cavity into the bloodstream (eg, buccal or sublingual administration). Compositions suitable for oral administration include solid, liquid, gel or powder formulations and have dosage forms such as tablets, troches, capsules, granules or powders. Compositions for oral administration can be formulated for immediate or modified release, including delayed or sustained release, optionally with an enteric coating. Liquid preparations can include solutions, syrups and suspensions, and can be used in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose or oil. The formulations may also include one or more emulsifying and/or suspending agents.

In tablet dosage forms, the drug may be present in an amount from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the dosage form. Additionally, the tablet may contain a disintegrant, from about 0.5% to about 35% by weight, more typically from about 2% to about 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

Suitable lubricants for tablets can range from about 0.1% to about 5% by weight and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium stearate, zinc stearate, or stearic acid Magnesium acid, sodium stearate fumarate, etc.

Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycols, sugars, gums, starches, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose and starch.

Suitable solubilizers for tablets can range from about 0.1% to about 3% by weight and include, but are not limited to, polysorbates, sodium lauryl sulfate, sodium lauryl sulfate, propylene carbonate, dimethacrylate Glycol Monoethyl Ether, Dimethyl Isosorbide, Castor Oil Polyethylene Glycol (Natural or Hydrogenated), HCOR ^™ (Nikkol), Oleyl Esters, Gelucire ^™ , Caprylic/Caprylic Mono/Diglycerides, Sorbitan Fats acid esters and Solutol HS ^™ .

parenteral administration

The compounds of the present disclosure can be administered directly into the bloodstream, muscle or internal organs. Suitable modes of parenteral administration include intravenous, intramuscular, intraarterial, intraperitoneal, intrathecal, intracranial, and the like. Suitable devices for parenteral administration include syringes (including needle and needle-free syringes) and infusion methods.

Compositions for parenteral administration can be formulated for immediate or modified release, including delayed or sustained release. Most parenteral preparations are aqueous solutions containing excipients including salts, buffers and isotonic agents. Parenteral formulations can also be prepared in dehydrated form (eg, by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable carrier, such as sterile water. Solubility enhancers can also be used in the preparation of parenteral solutions.

transdermal administration

The compounds of the present disclosure can be administered topically to the skin or transdermally. Formulations for such topical administration may include emulsions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical formulations may include water, alcohol, mineral oil, glycerol, polyethylene glycol, and the like. Topical or transdermal administration can also be performed by electroporation, iontophoresis, sonophoresis, and the like. Compositions for topical administration can be formulated for immediate or modified release, including delayed or sustained release.

combination therapy

Pharmaceutical compositions according to the present disclosure may contain one or more additional therapeutic agents, eg, to increase efficacy or reduce side effects. Thus, in some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents selected from active ingredients for the treatment or inhibition of diseases mediated directly or indirectly by HPK1. Examples of such active ingredients are, but are not limited to, agents for the treatment of cancer, metastasis, inflammation or autoimmune pathogenesis. In some embodiments, the compound of formula (I) is administered with an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA4 agent.

References for the preparation of pharmaceutical compositions

Methods of preparing pharmaceutical compositions for the treatment or prevention of diseases or disorders are well known in the art to which this disclosure pertains. For example, according to Handbook of Pharmaceutical Excipients (7th ^ed .), Remington: The Science and Practice of Pharmacy (20th ^ed .), Encyclopedia of Pharmaceutical Technology (3rd ^ed .) or Sustained and Controlled Release Drug Delivery Systems (1978) Pharmaceutically acceptable excipients, carriers, additives, etc. are selected and then mixed with the compounds of the present disclosure for use in formulating pharmaceutical compositions.

The present disclosure provides compounds having various pharmacological effects by inhibiting HPK1 activity, pharmaceutical compositions having the compounds as effective agents, medical uses, particularly for the treatment of diseases or conditions modulated by HPK1, and methods of treatment or prevention, including The compound is administered to a subject in need of such treatment or prevention. The compounds of the present disclosure and their pharmaceutically acceptable salts have good safety and high selectivity to HPK1, and thus exhibit excellent properties as drugs.

Compound preparation

The following Preparative Examples illustrate the preparation of intermediate compounds useful in the preparation of compounds of formula (I). The novel intermediate compounds and synthetic methods used to prepare the intermediate compounds described herein represent embodiments of the present invention.

Intermediate 1A. 1-(Tetrahydro-2H-pyran-2-yl)-5-(thiophen-2-yl)-1H-indazol-4-yl trifluoromethanesulfonate

Step 1) 3-Bromo-4-chloro-5-fluoro-2-methylaniline

To a solution of 3-bromo-5-fluoro-2-methylaniline (50 g, 245 mmol, 1 eq) in AcOH (100 mL) was added N-chlorosuccinimide (36 g, 270 mmol, 1.1 eq). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum and the residue was extracted with dichloromethane (200 mL*2). The combined organic layers were washed with saturated _NaHCO3 200 mL, dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The crude product was obtained as a black oil (66 g, crude).

Step 2) 4-Bromo-5-chloro-6-fluoro-1H-indazole

To a solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (25.8 g, 108 mmol, 1 eq) in AcOH (1.96 L, 0.05 M), H ₂ O (0.065 L, 1.5 M) was added Sodium nitrate (8.96 g, 130 mmol, 1.2 eq). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum and the residue was extracted with dichloromethane (1 L*2). The combined organic layers were washed with saturated _NaHCO3 (1 L), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The crude product was obtained as a brown solid (23.6 g, crude).

Step 3) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (1.98 g, 7.97 mmol, 1 eq) in THP (40 mL) was added 3,4-dihydro-2H-pyran (2.18 ml, 23.9 mmol, 3eq) and p-toluenesulfonic acid monohydrate (300mg, 1.59mmol, 0.2eq). The reaction mixture was stirred at 70°C for 14 hours. The reaction mixture was extracted with ethyl acetate and dried over _MgSO4 . The organic residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:0-4:1). 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.51 g, 4.54 mmol, 57% yield) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 8.00 (dd, J=9.3, 1.1 Hz, 1H), 5.85 (dd, J=9.6, 2.5 Hz, 1H), 3.87 ( d, J=12.6Hz, 1H), 3.79-3.72 (m, 1H), 2.38-2.30 (m, 1H), 2.04-1.94 (m, 2H), 1.77-1.55 (m, 3H).

Intermediate 1B. 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

Step 1) 4-Bromo-5-chloro-6-fluoro-7-iodo-1H-indazole

To a solution of 4-bromo-5-chloro-6-fluoro-lH-indazole (2 g, 8.02 mmol) in sulfuric acid (1.7 mL) was added N-iodosuccinimide (2.7 g, 12.03 mmol) portionwise. The mixture was stirred at 0°C for 3 hours. After the reaction was complete, the mixture was poured into ice water and quenched with solid NaOH, then extracted with dichloromethane. The combined organic residues were concentrated in vacuo. (2.99g, crude).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.91 (s, 1H), 8.27 (d, J=1.6 Hz, 1H).

Step 2) 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

To a solution of 4-bromo-5-chloro-6-fluoro-7-iodo-1H-indazole (2.99 g, 7.97 mmol, 1 eq) in THP (40 mL) was added 3,4-dihydro-2H-pyran ( 2.18ml, 23.9mmol, 3eq) and p-toluenesulfonic acid monohydrate (300mg, 1.59mmol, 0.2eq). The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was extracted with ethyl acetate and dried over _MgSO4 . The organic residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:0-4:1). 4-Bromo-5-chloro-6-fluoro-7-iodo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.64 g, 7.97 mmol, 60.7% yield) was obtained.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 5.80 (dd, J=9.9, 2.7Hz, 1H), 5.66 (s, 1H), 4.02 (t, J=6.6Hz, 1H), 3.85-3.70 (m, 1H), 2.33-2.21 (m, 1H), 2.08-1.91 (m, 2H), 1.79-1.45 (m, 4H).

Intermediate 1C. 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

Step 1) 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole

To a mixture of _HNO3 (12.63 g, 200.43 mmol, 9.02 mL, ₅ eq) in _H2SO4 (50 mL) stirred at 0 °C was slowly added 4-bromo-5-chloro-6-fluoro-1H-indazole ( 10 g, 40.09 mmol, 1 eq). After addition the mixture was stirred at 0°C for 2 hours. TLC (petroleum ether:ethyl acetate = 3:1) indicated that all reactants were consumed and a new major spot appeared. The mixture was poured into ice water, extracted with ethyl acetate (50 mL*3), the combined organic phases were dried over _Na2SO4 , filtered and the filtrate was concentrated to give ₄ -bromo-5-chloro-6-fluoro- as a yellow solid 7-Nitro-1H-indazole (12 g, crude).

Step 2) 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (2.34 g, 7.97 mmol, 1 eq) in THF (40 mL) was added 3,4-dihydro-2H-pyran (2.18ml, 23.9mmol, 3eq) and p-toluenesulfonic acid monohydrate (300mg, 1.59mmol, 0.2eq). The reaction mixture was stirred at 60°C for 14 hours. The reaction mixture was extracted with ethyl acetate and dried over _MgSO4 . The organic residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:0-4:1). Obtained 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.65 g, 4.35 mmol, 54.7% yield) .

Step 3) 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

To 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (600 mg, 1.58 mmol, 1 eq) in EtOH (5 mL) ) and H ₂ O (5 mL) were added NH ₄ Cl (508.66 mg, 9.51 mmol, 6 eq) and Fe (531.04 mg, 9.51 mmol, 6 eq) and the reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL*2), then the organic layer was dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC ( _SiO2 , petroleum ether/ethyl acetate = 1:1). 4-Bromo-5-chloro-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine (390 mg, 1.12 mmol, 70.59% yield) was obtained as a yellow oil Rate).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.41(s,1H),5.85(br s,2H),5.71(br d,J=8.0Hz,1H),4.00(br d,J=11.3Hz , 1H), 3.77-3.59 (m, 1H), 2.29-2.17 (m, 1H), 2.10-1.91 (m, 2H), 1.78-1.54 (m, 3H).

Intermediate 1D. 4-Bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-amine

Step 1) 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole

To a solution of Intermediate 1A (900 mg, 3.61 mmol, ₁ eq) in _H2SO4 (10 mL) (98% pure) at -15°C was added _HNO3 (419.69 mg, 4.33 mmol, 299.78 uL, 1.2 eq) dropwise ) (65% purity), then the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was slowly poured into ice water (20 mL), then the pH of the mixture was adjusted to pH=7 with saturated aqueous NaOH solution, then the mixture was extracted with ethyl acetate (30 mL*2), the combined organic layers were washed with Na ₂ SO ₄ Dry, filter and concentrate under reduced pressure to a residue. 4-Bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, crude) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.36 (br s, 1H), 8.37 (br s, 1H).

Step 2) 4-Bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (900 mg, 3.06 mmol, 1 eq) (crude) in DCM (10 mL) was added _TsOH.H2O (58.14 mg) , 305.64 umol, 0.1 eq) and DHP (771.27 mg, 9.17 mmol, 838.34 uL, 3 eq), then the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), and the mixture was washed with a saturated aqueous solution of NaHCO ₃ (15 mL*2), the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=40/1-25:1,4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyridine) Furan-2-yl)-1H-indazole at petroleum ether/ethyl acetate=40/1, 4-bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H- Pyran-2-yl)-2H-indazole was purified when petroleum ether/ethyl acetate=25/1). 4-Bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 528.29 umol, 17.28%) was obtained as a brown solid Yield). 4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (600 mg, 1.58 mmol, 51.85%) was obtained as a yellow solid Yield).

4-Bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 5.50 (dd, J=2.8, 7.8 Hz, 1H), 3.45-3.38 (m, 2H), 2.35-2.27 (m, 1H) ), 2.23-2.14 (m, 1H), 1.92 (td, J=4.6, 13.6Hz, 1H), 1.68 (ddt, J=4.0, 10.1, 13.9Hz, 1H), 1.59-1.36 (m, 2H).

4-Bromo-5-chloro-6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 5.86 (dd, J=2.7, 9.7 Hz, 1H), 4.08-3.96 (m, 1H), 3.81-3.68 (m, 1H) ), 2.28-2.14(m, 1H), 2.14-2.02(m, 1H), 2.02-1.89(m, 1H), 1.78-1.67(m, 1H), 1.64-1.56(m, 2H).

Step 3) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-amine

To 4-bromo-5-chloro-6-fluoro-7-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (200 mg, 528.29 umol, 1 eq) in EtOH (5 mL) ) and H ₂ O (5 mL) were added NH ₄ Cl (169.55 mg, 3.17 mmol, 6 eq) and Fe (177.03 mg, 3.17 mmol, 6 eq) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to remove EtOH, then the mixture was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL*2), then the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue thing. 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-amine (140 mg, crude) was obtained as a yellow solid.

Step 4) 4-Bromo-5-chloro-6-fluoro-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-amine

To 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-amine (120 mg, 344.24 umol) at ₀ °C under N , 1 eq) in THF (5 mL) was added portionwise NaH (34.42 mg, 860.59 umol, 60% pure, 2.5 eq), then the mixture was stirred at ₀ °C under N for 30 min, then MeI was added dropwise (293.16 mg, 2.06 mmol, 128.58 uL, 6 eq) and the reaction mixture was stirred at 20 °C for 12 h under _N2 . The reaction mixture was poured into a saturated aqueous solution of _NH4Cl (20 mL), then the mixture was extracted with ethyl acetate (20 mL*2), the combined organic layers _were dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC ( _SiO2 , petroleum ether/ethyl acetate=5:1). Intermediate IE (30 mg, 78.06 umol, 22.68% yield, 98% purity) was obtained as a yellow oil.

Intermediate 1E. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

To a solution of Intermediate 1B (100 mg, 0.218 mmol, 1 eq) in 2-methyl-2-butanol (1.09 mL) was added Xantphos Pd G3 (21 mg, 21.8 μmol, 0.1 eq) and Cs ₂ CO ₃ (142 mg, 0.436 mmol, 2.0 eq). The mixture was degassed and purged with _N2 3 times, then propan-2-amine (0.19 mL, 2.18 mmol, 10 eq) was added. The mixture was stirred in a sealed tube at 90°C for 3 hours. The reaction mixture was diluted with _H2O (40 mL), then the mixture was extracted with DCM (50 mL*3). The combined organic layers _were dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (product at hexane/ethyl acetate = 10/1) to afford Intermediate IE (47 mg, 0.120 mmol, 55% yield) as a beige solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 5.74 (dd, J=9.6, 2.5Hz, 1H), 5.29 (dd, J=9.9, 3.3Hz, 1H), 4.63- 4.57(m,1H),3.99(d,J=11.0Hz,1H),3.74-3.68(m,1H),2.23-2.17(m,1H),2.05-1.95(m,2H),1.74-1.57( m, 3H), 1.23-1.18 (m, 6H).

Intermediate 1F. 4-Bromo-5-chloro-6-fluoro-N-isopropyl-N-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-amine

To a solution of Intermediate 1E (600 mg, 1.54 mmol, 1.0 eq) in methanol (7.7 mL) was added formaldehyde (0.572 mL, 7.68 mmol, 5.0 eq) and acetic acid (88 μL, 1.54 mmol, 1.0 eq). The mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (290 mg, 4.61 mmol, 3.0 eq) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with _H2O and extracted with ethyl acetate (150 mL*3). The combined organic layers _were dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (product at hexane/ethyl acetate = 100/4) to afford Intermediate 1F (292 mg, 0.722 mmol, 47% yield) as a brown oil.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 5.75 (dd, J=9.3, 2.7 Hz, 1H), 4.14-4.05 (m, 1H), 4.00-3.93 (m, 1H) ),3.78-3.67(m,1H),2.92(d,J＝4.4Hz,3H),2.23-2.20(m,1H),2.05-1.95(m,2H),1.75-1.60(m,3H), 1.17 (d, J=6.6 Hz, 6H).

Intermediate 1G. 4-Bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazol-7-amine

Step 1) 4-Bromo-5-chloro-6-fluoro-1H-indazol-7-amine

To a solution of 4-bromo-5-chloro-6-fluoro-7-nitro-1H-indazole (12 g, 40.75 mmol, 1 eq) in EtOH (100 mL) and H ₂ O (40 mL) was added Fe (6.83 g) , 122.26 mmol, 3 eq) and NH ₄ Cl (6.54 g, 122.26 mmol, 3 eq). The reaction mixture was heated to 80°C and reacted for 2 hours. The reaction mixture was filtered through a celite filter cake and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1-3/1). 4-Bromo-5-chloro-6-fluoro-lH-indazol-7-amine (5 g, 18.90 mmol, 46.39% yield) was obtained as a yellow solid.

Step 2) N-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)acetamide

To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazol-7-amine (3 g, 11.34 mmol, 1 eq) in AcOH (30 mL) was added _Ac2O (1.39 g, 13.61 mmol, 1.27 mL) , 1.2eq), the reaction mixture was heated to 80°C and reacted for 3 hours. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1-4/1) to obtain N-(4-bromo-5-chloro-6-fluoro-1H-indole as a yellow solid) oxazol-7-yl)acetamide (3 g, 9.79 mmol, 86.29% yield).

Step 3) 4-Bromo-5-chloro-N-ethyl-6-fluoro-1H-indazol-7-amine

To a solution of LAH (520.00 mg, 13.70 mmol, 1.5 eq) in THF (50 mL) at 0 °C under _N2 was added dropwise N-(4-bromo-5-chloro-6-fluoro-1H-indazole- 7-yl)acetamide (2.8 g, 9.13 mmol, 1 eq) in THF (100 mL) was added and the reaction mixture was warmed to 25 °C and reacted for 16 hours. The mixture was poured into water (500 mL), extracted with ethyl acetate (100 mL*2), the combined organic phases _were dried over _Na2SO4 , filtered and the filtrate concentrated to give the crude product. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=50/1-2/1) to obtain 4-bromo-5-chloro-N-ethyl-6-fluoro-1H as a yellow solid -Indazol-7-amine (1 g, 3.42 mmol, 37.42% yield).

Step 4) 4-Bromo-5-chloro-N-ethyl-6-fluoro-N-methyl-1H-indazol-7-amine

To 4-bromo-5-chloro-N-ethyl-6-fluoro-1H-indazol-7-amine (1.4g, 4.79mmol, 1eq) and HCHO (718.48mg, 23.93mmol, 659.16uL, 5eq) To the MeOH (50 mL) solution was added NaBH3CN (902.21 mg, 14.36 mmol, 3 eq) and AcOH (287.38 mg, 4.79 mmol, 273.70 uL, 1 eq). The reaction mixture was stirred at 25°C for 16 hours. The solvent was removed under vacuum. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=50/1-5/1) to obtain 4-bromo-5-chloro-N-ethyl-6-fluoro-N as a white solid - Methyl-1H-indazol-7-amine (1.4 g, 4.57 mmol, 95.42% yield).

Intermediate 1H. 4-Bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.50 mmol, 1 eq) in THF ( 10 mL) was added dropwise LDA (2M, 1.87 mL, 2.5 eq). After the addition, the mixture was stirred at this temperature for 2.5 hours, then MeI (319.12 mg, 2.25 mmol, 139.97 uL, 1.5 eq) was added dropwise at -78 °C. And the resulting mixture was stirred at 20°C for 16 hours. The mixture was poured into saturated _NH4Cl and extracted with EA 20 mL. The organic layer was concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1-10/1). We obtained the desired product as a white solid, 4-bromo-5-chloro-6-fluoro-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.38 g, 1.09 mmol, 72.93% yield).

Intermediate II. 4-Bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazol-7-amine

Step 1) 4-Bromo-6-fluoro-7-nitro-1H-indazole

To a solution of 4-bromo-6-fluoro-1H-indazole (10 g, 46.51 mmol, 1 eq) in H ₂ SO ₄ (80 mL) (98% purity) at 0° C. was added KNO ₃ (4.70 g, 46.51 g) portionwise mmol, 1 eq), then the mixture was stirred at 0 °C for 1 hour. The reaction mixture was then poured into ice water (200 mL), and the mixture was extracted with ethyl acetate (100 mL*2), the combined organic layers were washed with saturated aqueous NaHCO ₃ (100 mL*2) and brine (100 mL), washed with _{Na2SO 4} Dry, filter and concentrate under reduced pressure to a residue. The residue was chromatographed on silica gel (200-300 mesh silica gel, petroleum ether/ethyl acetate = 15/1-1/1, the product 4-bromo-6-fluoro-7-nitro-1H-indazole in petroleum ether/acetic acid ethyl ester = 8/1) was purified to give 4-bromo-6-fluoro-7-nitro-lH-indazole (2.7 g, 10.38 mmol, 22.32% yield) and crude product as a yellow solid. The crude product was purified by MPLC (petroleum ether/ethyl acetate) to give 4-bromo-6-fluoro-7-nitro-lH-indazole (3.57 g, 13.73 mmol, 29.52% yield) as a yellow solid.

Step 2) 4-Bromo-6-fluoro-5-iodo-7-nitro-1H-indazole

To a solution of 4-bromo-6-fluoro-7-nitro-1H-indazole (2.7 g, 10.38 mmol, 1 eq) in H ₂ SO ₄ (30 mL) at 25 °C was added NIS (7.01 g, 31.15 mmol, 3eq). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was quenched with ice water (50 mL). The mixture was then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with aqueous Na2SO3 (20 mL* ₂ ), aqueous _NaHCO3 (20 mL* ₂ ) and brine (20 mL), dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to give 4 as a yellow solid -Bromo-6-fluoro-5-iodo-7-nitro-1H-indazole (3.4 g, 8.81 mmol, 84.85% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.28 (br s, 1H), 8.30 (s, 1H).

Step 3) 4-Bromo-6-fluoro-5-iodo-1H-indazol-7-amine

To a solution of 4-bromo-6-fluoro-5-iodo-7-nitro-1H-indazole (3.4 g, 8.81 mmol, 1 eq) in EtOH (50 mL) and H ₂ O (25 mL) was added NH ₄ Cl ( 2.83 g, 52.86 mmol, 6 eq), then Fe (2.95 g, 52.86 mmol, 6 eq) was added portionwise at 60°C. The mixture was stirred at 80°C for 1 hour. The reaction mixture was filtered hot through celite. The filtrate was then concentrated under vacuum to remove EtOH. The resulting aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (MPLC, petroleum ether/ethyl acetate=5/1-2/1, product appeared at petroleum ether/ethyl acetate=2/1) to give 4-bromo- 6-Fluoro-5-iodo-lH-indazol-7-amine (2.2 g, 6.18 mmol, 70.16% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.09 (br s, 1H), 7.86 (d, J=1.7 Hz, 1H), 5.62 (s, 2H).

Step 4) 4-Bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazol-7-amine

To a solution of 4-bromo-6-fluoro-5-iodo-1H-indazol-7-amine (2.2 g, 6.18 mmol, 1 eq) in MeOH (50 mL) was added AcOH (1.11 g, 18.54 mmol, 1.06 mL, 3 eq) ), HCHO (5.02 g, 61.81 mmol, 4.60 mL, 10 eq), then NaBH ₃ CN (3.88 g, 61.81 mmol, 10 eq) was added portionwise at 40°C. Release the gas and raise the temperature. The suspension was stirred at 25°C for 16 hours. The reaction mixture was poured into water (50 mL), then the mixture was concentrated to remove MeOH, then the mixture was extracted with ethyl acetate (50 mL*2), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether/ethyl acetate = 15/1-8/1, product appeared at petroleum ether/ethyl acetate = 8/1) to give the product as an off-white solid. 4-Bromo-6-fluoro-5-iodo-N,N-dimethyl-lH-indazol-7-amine (2.05 g, 5.34 mmol, 86.37% yield).

Step 5) 4-Bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazol-7-amine

4-Bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazol-7-amine (1.2 g, 3.13 mmol, 1 eq), NaSMe (1.2 g, 3.13 mmol, 1 eq) were added to a 100 mL flask equipped with a magnetic stirring bar. (328.56mg, 4.69mmol, 1.5eq), Xantphos (361.65mg, 625.02umol, 0.2eq), K2CO3 ( _1.30g , _9.38mmol , 3eq), dioxane (20mL) and Pd2(dba _{) 3} (286.17mg, 312.51umol, 0.1eq). The bottle was evacuated and backfilled with nitrogen. The mixture was then stirred at 90°C for 16 hours under nitrogen atmosphere. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether/ethyl acetate = 20/1-8/1, product appeared at petroleum ether/ethyl acetate = 10/1) to give an orange solid 4-Bromo-6-fluoro-N,N-dimethyl-5-(methylthio)-1H-indazol-7-amine (540 mg, 1.78 mmol, 56.81% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ13.59(br s, 1H), 8.00(d, J=1.6Hz, 1H), 2.91(d, J=2.4Hz, 6H), 2.39(s, 3H) ).

Intermediate 1J. 4-Bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazol-7-amine

To 4-bromo-6-fluoro-5-iodo-N,N-dimethyl-1H-indazol-7-amine (1.0 g, 2.61 mmol, 1 eq) and methyl 2,2-difluoro-2- To a solution of (fluorosulfonyl)acetate (1.00 g, 5.22 mmol, 664.45 uL, 2 eq) in DMF (10 mL) was added CuI (994.63 mg, 5.22 mmol, 2 eq). The mixture was stirred at 100 °C for 6 h under _N2 atmosphere. The reaction mixture was filtered, and the filtrate was diluted with water 50 mL and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL* ₃ ), dried over anhydrous _Na2SO4 , filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0-10:1). 4-Bromo-6-fluoro-N,N-dimethyl-5-(trifluoromethyl)-1H-indazol-7-amine (502 mg, 1.54 mmol, 58.91% yield) was obtained as a yellow solid.

Intermediate 1K. 4-Bromo-5-ethyl-6-fluoro-1H-indazole

Step 1) 4-Bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole

To a solution of diisopropylamine (132.75 mg, 1.31 mmol, 185.41 uL, 1.2 eq) in THF (5 mL) at -78 °C under N atmosphere was slowly added n-butyllithium ( _2.5 M, 481.04 uL, 1.1 eq) 0.5 hours. A solution of 4-bromo-6-fluoro-2-triphenyl-2H-indazole (500 mg, 1.09 mmol, 1 eq) in THF (2 mL) was then added dropwise to the solution. After the mixture was stirred at -78 °C for 0.5 h, a solution of EtI (204.62 mg, 1.31 mmol, 104.93 uL, 1.2 eq) in THF (2 mL) was added to the mixture, and the solution was heated to 15 °C under _N2 atmosphere Stir for 2 hours. The reaction mixture was quenched by adding 3 mL of saturated aqueous _NH4Cl at 15°C, diluted with 20 mL of water and extracted with ethyl acetate (30 mL*2). The combined organic layers were washed with brine (30 mL* ₂ ), dried over _Na2SO4 , filtered and the filtrate was concentrated under reduced pressure to a residue. 4-Bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole (500 mg, crude) was obtained as a yellow solid.

Step 2) 4-Bromo-5-ethyl-6-fluoro-1H-indazole

To a solution of 4-bromo-5-ethyl-6-fluoro-2-triphenyl-2H-indazole (500 mg, 1.03 mmol, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL) , 26.22eq). The mixture was stirred at 15°C for 4 hours. The pH of the reaction mixture was adjusted to 7 with saturated aqueous NaHCO ₃ , and the mixture was extracted with dichloromethane (30 mL*2). The combined organic layers were washed with brine (30 mL* ₂ ), dried over _Na2SO4 , filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%-70%, 10 minutes). The separation was concentrated under reduced pressure to remove ACN, and the pH of the aqueous solution was adjusted to 7 with saturated aqueous NaHCO ₃ . The aqueous solution was extracted with ethyl acetate (10 mL*2). The combined organic layers were washed with brine (10 mL* ₂ ), dried over _Na2SO4 , filtered and the filtrate was concentrated under reduced pressure to a residue. 4-Bromo-5-ethyl-6-fluoro-lH-indazole (70 mg, 287.98 umol, 27.96% yield) was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ13.39(br s,1H),8.01-7.98(m,1H),7.41(d,J=9.9Hz,1H),2.83(dq,J=2.4, 7.5Hz, 2H), 1.14 (t, J=7.5Hz, 3H).

Intermediate 1L. 4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

Step 1) 6-Fluoro-5-nitro-1H-indazole

To a solution of 6-fluoro-1H-indazole (4.4 g, 32.32 mmol, 1 eq) in H ₂ SO ₄ (30 mL) at -15 °C was added HNO ₃ (2.44 g, 38.79 mmol, 1.75 mL, 1.2 eq) dropwise ), the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was slowly poured into ice water (100 mL), then the mixture was extracted with ethyl acetate (100 mL*2), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 6- as a yellow solid. Fluoro-5-nitro-1H-indazole (5.4 g, crude).

Step 2) 6-Fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 6-fluoro-5-nitro-1H-indazole (4.9 g, 27.05 mmol, 1 eq) (crude) in DCM (50 mL) was added DHP (6.83 g, 81.16 mmol, 7.42 mL, 3 eq) and TsOH. _H2O (514.60 mg, 2.71 mmol, 0.1 eq) and the reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO ₃ (100 mL), then the mixture was extracted with dichloromethane (50 mL*2), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=20/1-15:1) to obtain 6-fluoro-5-nitro-1-(tetrahydro-2H-pyridine as a yellow solid) Furan-2-yl)-1H-indazole (3 g, 11.31 mmol, 41.81% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (d, J=7.3 Hz, 1H), 8.41 (s, 1H), 7.97 (d, J=12.1 Hz, 1H), 5.90 (dd, J= 2.1, 9.7Hz, 1H), 3.94-3.85(m, 1H), 3.82-3.72(m, 1H), 2.43-2.28(m, 1H), 2.10-1.93(m, 2H), 1.82-1.34(m, 3H).

Step 3) 6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

To ₆ -fluoro-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.9 g, 10.93 mmol, 1 eq) in MeOH (30 mL) under N atmosphere To the solution was added wet Pd/C (300 mg, 10% purity). The suspension was degassed and purged with H ₃ times. The mixture was stirred under _H2 (15 Psi) at 15°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=15/1-8:1). 6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine was obtained as a brick red solid (1.5 g, 5.87 mmol, 53.65% yield, 92% purity) .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (s, 1H), 7.43 (d, J=11.6 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 5.66 (dd, J= 2.3,9.7Hz,1H),4.91(s,2H),3.85(br d,J=12.1Hz,1H),3.77-3.62(m,1H),2.42-2.27(m,1H),2.07-1.96( m, 1H), 1.95-1.86 (m, 1H), 1.76-1.63 (m, 1H), 1.59-1.51 (m, 2H); LCMS (electrospray) m/z 236.1 (M+H)+.

Step 4) 4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

To a solution of 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1.45 g, 5.67 mmol, 1 eq) in MeCN (10 mL) was partitioned at 0 °C NBS (1.21 g, 6.80 mmol, 1.2 eq) was added in batches. And the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated to obtain a residue. The residue was then dissolved in ethyl acetate (30 mL), the mixture was washed with brine (15 mL*2), the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1). 4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1.3 g, 4.14 mmol, 72.98% yield) was obtained as a brown solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.80(s, 1H), 7.60(d, J=10.6Hz, 1H), 5.71(dd, J=2.5, 9.6Hz, 1H), 5.15(s, 2H), 3.88-3.82(m, 1H), 3.76-3.68(m, 1H), 2.36-2.27(m, 1H), 2.02(brdd, J=4.6, 8.5Hz, 1H), 1.96-1.90(m, 1H), 1.76-1.65 (m, 1H), 1.60-1.52 (m, 2H).

Intermediate 1M. 3-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol

Step 1) 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbaldehyde

To a mixture of Intermediate 1A (3 g, 8.99 mmol, 1 eq) in THF (60 mL) at -78 °C under N ₂ was added LDA (2M, 17.99 mL, 4 eq) dropwise. The mixture was stirred at -78°C for 1 hour. Then, a solution of HCO ₂ Et (3.17 g, 35.97 mmol, 3.52 mL, 4 eq) in THF (8 mL) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched by addition of saturated _NH4Cl solution (20 mL) at -78°C, then extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL* ₂ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1-20/1). 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbaldehyde (2.78 g, 7.69 mmol, 85.49 g) was obtained as an off-white solid %Yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.40(s,1H),8.35(s,1H),6.09(dd,J=2.6,8.9Hz,1H),3.71-3.63(m,1H), 3.63-3.52(m, 1H), 2.42-2.30(m, 1H), 2.21-2.10(m, 1H), 2.07-1.95(m, 1H), 1.77-1.63(m, 2H), 1.60-1.40(m , 2H); LCMS (electrospray) m/z 278.9 (M+H)+.

Step 2) 1-(4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)but-3-ene-1 -alcohol

To 4-bromo- ₅ -chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-7-carbaldehyde (2.2 g, 6.08 mmol, 1 eq) in THF (60 mL) was added allylmagnesium bromide (1 M, 9.13 mL, 1.5 eq) dropwise. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by addition of saturated _NH4Cl solution (20 mL) at 0 °C, then extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1-5/1). 1-(4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7-yl)butan-3- was obtained as a colorless oil En-1-ol (2 g, 4.95 mmol, 81.43% yield).

¹ H NMR(400MHz, DMSO-d ₆ )δ8.25-8.21(m,1H),8.20-8.18(m,1H),6.61(br d,J=9.0Hz,1H),6.23(d,J= 4.0Hz, 1H), 6.18 (br d, J=8.3Hz, 1H), 5.95 (d, J=5.0Hz, 1H), 5.90-5.75 (m, 2H), 5.36 (dt, J=4.3, 7.5Hz) ,1H),5.30(td,J＝5.9,7.9Hz,1H),5.10-4.97(m,4H),3.97(br d,J＝11.5Hz,1H),3.89(br d,J＝11.3Hz, 1H), 3.69-3.55(m, 2H), 2.87-2.74(m, 2H), 2.70-2.55(m, 4H), 2.06(br d, J=10.8Hz, 3H), 1.96-1.87(m, 1H) ), 0.90-0.78 (m, 1H); LCMS (electrospray) m/z 302.9 (M+H)+.

Step 3) 4-Bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole

Under N at -20 °C, 1-( ₄ -bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-7- yl)but-3-en-1-ol (2 g, 4.95 mmol, 1 eq) in DCM (20 mL) was added dropwise a mixture of Br ₂ (1.19 g, 7.43 mmol, 383.11 uL, 1.5 eq) in DCM (2 mL) . The mixture was stirred at -10°C for 3 hours. _The mixture was quenched by the addition of Na2SO3 solution ( ₃₀ mL), then diluted with DCM (30 mL). The organic layer was washed with Na ₂ SO ₃ solution (30 mL*2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was dissolved in MeOH (15 mL), then K2CO3 (2.05 _g , 14.86 mmol, ₃ eq) was added and the resulting mixture was stirred at 20 °C for 16 h. The reaction was quenched by adding water (20 mL), extracted with EA (30 mL* ₃ ), dried over _Na2SO4 , filtered and concentrated to obtain a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=10/1-3:1). The crude product was purified by reverse phase HPLC (0.1% FA conditions). 4-Bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-lH-indazole (300 mg, 752.91 umol, 15.20% yield) was obtained as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.44-13.37(m, 2H), 8.14-8.11(m, 2H), 5.71-5.67(m, 1H), 5.44(dt, J=1.2, 7.5Hz) ,1H),4.97(s,1H),4.83-4.76(m,2H),4.47(dd,J=3.7,10.1Hz,1H),4.22(dd,J=5.5,10.1Hz,1H),4.15( dd, J=2.3, 10.6 Hz, 1H), 3.20-3.13 (m, 1H), 2.69-2.64 (m, 1H), 2.34-2.27 (m, 2H); LCMS (electrospray) m/z 398.8 (M +H)+.

Step 4) 3-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentyl acetate

To 4-bromo-7-(3-bromocyclopentyl)-5-chloro-6-fluoro-1H-indazole (100 mg, 250.97 μmol, 1 eq) in DMSO ( ₂ mL) at 20 °C under N ) mixture was added in one portion of KOAc (73.89 mg, 752.91 μmol, 3 eq). The mixture was then heated to 70°C and stirred for 3 hours. Water (15 mL) was added to quench the reaction, then extracted with EA (20 mL*3), the combined organic layers were washed with brine (20 mL* ₂ ), dried over _Na2SO4 , filtered and concentrated to give a residue. 3-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentyl acetate (100 mg, crude, brown oil) was used in the next step without further purification.

LCMS (electrospray) m/z 378.8 (M+H)+.

Step 5) 3-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol

To 3-(4-bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentyl acetate (80 mg, 211.87 umol, 1 eq) under N at ₂₀ °C To a mixture of MeOH ( ₄ mL) and _H2O (0.8 mL) was added K2CO3 ( _442.15 mg, 3.20 mmol, 15.1 eq) in one portion. The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched by adding water (15 mL) at 20°C, then extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL*1), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1-1/2). 3-(4-Bromo-5-chloro-6-fluoro-1H-indazol-7-yl)cyclopentan-1-ol (50 mg, 149.01 umol, 70.33% yield) was obtained as a white solid.

LCMS (electrospray) m/z 336.9 (M+H)+.

Intermediate 1N. 4-Bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine

Step 1) 5-Fluoro-2-iodo-4-(trifluoromethyl)aniline

To a solution of 3-fluoro-4-(trifluoromethyl)aniline (4 g, 22.33 mmol, 1 eq) in MeCN (40 mL) at 15 °C was added NIS (5.53 g, 24.57 mmol, 1.1 eq), then the reaction mixture was added Stir at 15°C for 15 hours. The reaction mixture was diluted with _H2O (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers _were dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. 5-Fluoro-2-iodo-4-(trifluoromethyl)aniline (5.6 g, crude) was obtained as a brown oil.

LCMS (electrospray) m/z 305.9 (M+H)+.

Step 2) 5-Fluoro-2-methyl-4-(trifluoromethyl)aniline

To 5-fluoro-2-iodo-4-(trifluoromethyl)aniline (6.0 g, 19.67 mmol, 1 eq) and 2,4,6-trimethyl-1,3,5,2 at 15 °C ,4,6-Trioxaborane (8.82g, 29.51mmol, 9.82mL, 42% purity, 1.5eq) in DME (60mL) solution was added Pd( _PPh3 ) ₄ (1.14g, 983.57umol, 0.05eq) ) and K ₂ CO ₃ (8.16 g, 59.01 mmol, 3 eq), then the reaction mixture was stirred at 100 °C for 60 h. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=5/1-3/1, petroleum ether/ethyl acetate=2:1, Rf=0.3). 5-Fluoro-2-methyl-4-(trifluoromethyl)aniline (1.6 g, 4.06 mmol, 20.64% yield, 49% purity) was obtained as a yellow oil.

LCMS (electrospray) m/z 194.1.9 (M+H)+.

Step 3) 6-Fluoro-5-(trifluoromethyl)-1H-indazole

To a solution of 5-fluoro-2-methyl-4-(trifluoromethyl)aniline (1 g, 5.18 mmol, 1 eq) in AcOH (15 mL) at 0 °C was added NaNO ₂ (357.25 mg, 5.18 mmol, 1 eq) and _H2O (3 mL), then the reaction mixture was stirred at 15 °C for 2 h. The reaction was quenched by the addition of _H2O (60 mL) at 20 °C, and the resulting mixture was extracted with EtOAc (50 mL*3). The combined organic layers were washed with _H2O (50 mL* ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO2, petroleum ether/ethyl acetate=10/1-5/1, petroleum ether/ethyl acetate=3:1, Rf=0.5). 6-Fluoro-5-(trifluoromethyl)-lH-indazole (500 mg, 2.45 mmol, 47.31% yield) was obtained as a yellow solid.

LCMS (electrospray) m/z 205.2 (M+H)+.

Step 4) 6-Fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole

To a solution of 6-fluoro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.45 mmol, 1 eq) in _H2SO4 ( ₅ mL, 95% purity) at 0 °C was added _KNO3 (249 mg, 2.46 mmol, 1.01 eq), then the reaction mixture was stirred at 15 °C for 15 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were treated with saturated sodium bicarbonate solution to pH= ₇ , dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. 6-Fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole (500 mg) was obtained as a yellow solid.

LCMS (electrospray) m/z 250.2 (M+H)+.

Step 5) 6-Fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole

To a solution of 6-fluoro-7-nitro-5-(trifluoromethyl)-1H-indazole (500 mg, 2.01 mmol, 1 eq) in THF (10 mL) at 0 °C was added PPTS (50.44 mg, 200.71 mg) umol, 0.1 eq) and DHP (844.13 mg, 10.04 mmol, 917.53 uL, 5 eq), then the reaction mixture was stirred at 60°C for 15 hours. The reaction mixture was diluted with solvent _H2O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with _H2O (50 mL* ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. 6-Fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole (1 g, crude) was obtained as a yellow oil.

Step 6) 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine

To 6-fluoro-7-nitro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole (800 mg, 2.40 mmol, 1 eq) and H ₂ O (2 mL) in EtOH (10 mL) were added NH ₄ Cl (642.08 mg, 12.00 mmol, 5 eq) and Fe (268.13 mg, 4.80 mmol, 2 eq), then the reaction mixture was stirred at 60 °C 1 hour. The reaction mixture was diluted with _H2O (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with H ₂ O (30 mL*2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=10/1-5/1, petroleum ether:ethyl acetate=3:1, Rf=0.3). 6-Fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine (500 mg, 1.65 mmol, 68.68%) was obtained as a yellow solid Yield).

LCMS (electrospray) m/z 220.2 (M+H)+.

Step 7) 4-Bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine

To 6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine (200 mg, 659.51 umol, 1 eq) at 20 °C To a solution of DMF (1 mL) was added NBS (129.12 mg, 725.46 umol, 1.1 eq), and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with H ₂ O (10 mL*2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. 4-Bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine (120 mg, crude) was obtained as a yellow solid ).

LCMS (electrospray) m/z 297.9 (M+H)+.

Step 8) 4-Bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazol-7-amine

To 4-bromo-6-fluoro-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine (100 mg, 335.53 umol, 1eq) in MeOH (1mL) was added AcOH (40.30mg, 671.06umol, 38.38uL, 2eq) and acetone (97.44mg, 1.68mmol, 123.34uL, 5eq) followed by _NaBH3CN (105.42mg, 1.68 mmol, 5eq) and the reaction mixture was stirred at 20°C for 2 hours. Then, acetone (97.44mg, 1.68mmol, 123.34uL, 5eq), _NaBH3CN (105.43mg, 1.68mmol, 5eq) and AcOH (60.45mg, 1.01mmol, 57.57uL, 3eq) were added to the mixture, and the The reaction mixture was stirred at 20°C for 20 hours. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with H ₂ O (10 mL*2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate=3:1, Rf=0.4). 4-Bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazol-7-amine was obtained as a white solid (60 mg, 165.83 umol, 49.42% yield, 94% purity ).

LCMS (electrospray) m/z 340.1 (M+H)+.

Step 9) 4-Bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazol-7-amine

To 4-bromo-6-fluoro-N-isopropyl-5-(trifluoromethyl)-1H-indazol-7-amine (50 mg, 147.01 umol, 1 eq) in THF (1 mL) at 0 °C To the solution was added PPTS (3.69 mg, 14.70 umol, 0.1 eq) and DHP (61.83 mg, 735.05 umol, 67.21 uL, 5 eq) and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with _H2O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with _H2O (50 mL* ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=5:1, Rf=0.6). 4-Bromo-6-fluoro-N-isopropyl-2-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-2H-indazole-7 was obtained as a yellow oil - Amine (50 mg, 117.86 umol, 80.17% yield).

LCMS (electrospray) m/z 424.1 (M+H)+.

Intermediate 1O. 4-Bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Step 1) 3-Bromo-5-fluoro-2-methylaniline

To a mixture of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (23 g, 98.28 mmol, 1 eq) in EtOH (80 mL) and H ₂ O (80 mL) was added Fe (27.44 g, 491.41 mmol) , 5 eq) and NH ₄ Cl (26.29 g, 491.41 mmol, 5 eq). The mixture was stirred at 100°C for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with DCM (50 mL*3). The combined organic phases were washed with brine (50 mL*2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue to give 3-bromo-5-fluoro-2-methylaniline (20.6 oz.) as a yellow liquid g, crude product).

¹ H NMR(400MHz, DMSO-d ₆ )δ6.59(br d,J=8.4Hz,1H),6.42(br d,J=11.2Hz,1H),5.51(br s,2H),2.09(s , 3H).

Step 2) 3-Bromo-5-fluoro-4-iodo-2-methylaniline

To a mixture of 3-bromo-5-fluoro-2-methylaniline (18 g, 88.22 mmol, 1 eq) (crude) in _CH3CN (150 mL) at 0 °C was added NIS (19.85 g, 88.22 mmol, 1eq). The mixture was stirred at 30°C for 3 hours. After 3 hours, LCMS showed residual compound 2 and the desired amount was also detected. The mixture was then stirred at 30°C for a further 12 hours. LCMS showed no compound 2 remaining and one major peak with the expected amount was detected. The mixture was quenched with saturated Na2SO3 ( ₂₀₀ mL) and the resulting mixture was extracted with EtOAc (50 mL* ₃ ). The combined organic phases were washed with brine (50 mL* ₂ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate=50/1, 30/1; TLC (petroleum ether:ethyl acetate=10:1; Rf=0.28)) to give a brown color 3-Bromo-5-fluoro-4-iodo-2-methylaniline as a solid (22 g, 66.68 mmol, 75.58% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.55 (d, J=10.5 Hz, 1H), 5.67 (s, 2H), 2.25 (d, J=0.8 Hz, 3H).

Step 3) 4-Bromo-6-fluoro-5-iodo-1H-indazole

To a mixture of 3-bromo-5-fluoro-4-iodo-2-methylaniline (22 g, 66.68 mmol, 1 eq) in CH ₃ COOH (200 mL) at 0 °C was added dissolved water (40 mL) in NaNO ₂ ( 5.52g, 80.02mmol, 1.2eq). The mixture was stirred at 30°C for 16 hours. The mixture was poured into saturated _NaHCO3 (1000 mL) and the resulting mixture was extracted with EtOAc (200 mL*3). The combined organic phases were washed with brine (100 mL* ₂ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 15/1, 5/1) to give 4-bromo-6-fluoro-5-iodo-1H-indazole as a brown solid (7.5 g, 22.00 mmol, 32.99% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.58 (br s, 1H), 8.00 (s, 1H), 7.51 (d, J=8.1 Hz, 1H), 3.32 (s, 1H).

Step 4) 4-Bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 4-bromo-6-fluoro-5-iodo-1H-indazole (7.5 g, 22.00 mmol, 1 eq) and 4-methylbenzenesulfonic acid hydrate (418.47 mg, 2.20 mmol, 0.1 eq) in DCM (100 mL ) mixture was slowly added DHP (5.55 g, 66.00 mmol, 6.03 mL, 3 eq). The mixture was stirred at 30°C for 1 hour. The mixture was washed with saturated _NaHCO3 (30 mL*3) and brine (30 mL*3). The organic phase was dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 100/1, 50/1) to give 4-bromo-6-fluoro-5-iodo-1-(tetrakis) as a yellow solid Hydro-2H-pyran-2-yl)-1H-indazole (7.4 g, 17.41 mmol, 79.14% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.80 (dd, J=0.7, 8.4Hz, 1H), 5.83 (dd, J=2.4, 9.6Hz, 1H), 3.88- 3.85(m, 1H), 3.80-3.70(m, 2H), 2.40-2.27(m, 1H), 2.07-1.94(m, 2H), 1.81-1.63(m, 2H), 1.62-1.53(m, 2H) ).

Step 5) 4-Bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 4-bromo- ₆ -fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.53 mmol, 1 eq) and cyclopropane under N2 To a mixture of boronic acid (303.14 mg, 3.53 mmol, 1 eq) in dioxane (10 mL) and H ₂ O (2.5 mL) was added Na ₂ CO ₃ (748.10 mg, 7.06 mmol, 2 eq) and Pd(dppf)Cl ₂ (258.23 mg, 352.91 μmol, 0.1 eq). The mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=20:1) to give 4-bromo-5-cyclopropyl-6-fluoro-1-(tetrahydro-2H-pyran as a colorless oil -2-yl)-1H-indazole (0.21 g, 619.10 umol, 17.54% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J=0.6 Hz, 1H), 7.20 (d, J=10.4 Hz, 1H), 5.61 (dd, J=2.8, 9.1 Hz, 1H), 4.03 -3.94(m, 1H), 3.76-3.69(m, 1H), 2.55-2.42(m, 1H), 2.19-2.06(m, 2H), 1.91-1.86(m, 1H), 1.81-1.64(m, 3H), 1.12-1.05 (m, 2H), 0.87-0.81 (m, 2H).

Intermediate 1P. 4-Bromo-6-fluoro-5-isopropyl-1H-indazole

Step 1) 4-Bromo-6-fluoro-5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 4-bromo- ₆ -fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.5 g, 3.53 mmol, 1 eq) and trifluoro under N2 To a mixture of potassium (isopropenyl)borohydride (626.67 mg, 4.23 mmol, 1.2 eq) in dioxane (10 mL) and H ₂ O (2 mL) was added Pd(dppf)Cl ₂ (258.23 mg, 352.91 umol, 0.1 eq) and _Na2CO3 (748.10 mg, 7.06 mmol, ₂ eq). The mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate=100/1, 50/1; TLC (petroleum ether:ethyl acetate=10:1; Rf=0.61)) to obtain 0.9 g of yellow oil. This oil was purified by prep-TLC (petroleum ether:ethyl acetate=20:1) to give 4-bromo-6-fluoro-5-(prop-1-en-2-yl)-1- as a yellow oil (Tetrahydro-2H-pyran-2-yl)-1H-indazole (0.55 g, 1.62 mmol, 45.94% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ 8.00 (d, J=0.6Hz, 1H), 7.28 (d, J=0.9Hz, 0.5H), 7.26 (d, J=0.7Hz, 0.5H), 5.64 (dd, J=2.8, 9.0Hz, 1H), 5.46(t, J=1.6Hz, 1H), 5.01(s, 1H), 4.05-3.97(m, 1H), 3.80-3.69(m, 1H), 2.57-2.42 (m, 1H), 2.19-2.09 (m, 2H), 2.07 (s, 3H), 1.81-1.66 (m, 4H).

Step 2) 4-Bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 4-bromo- ₆ -fluoro-5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.4 g, 1.18 mmol, 1 eq) in MeOH (10 mL) was added _PtO2 . The suspension was degassed under vacuum and purged with _H2 several times. The mixture was stirred under _H2 (15 Psi) at 30°C for 2.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether/ethyl acetate = 50/1) to give 4-bromo-6-fluoro-5-isopropyl-1-(tetrakis) as a colorless oil Hydrogen-2H-pyran-2-yl)-1H-indazole (0.3 g, 879.20 umol, 74.56% yield).

Step 3) 4-Bromo-6-fluoro-5-isopropyl-1H-indazole

To a solution of 4-bromo-6-fluoro-5-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.3 g, 879.20 umol, 1 eq) in DCM (1 mL) To this was added TFA (2.30 g, 20.14 mmol, 1.49 mL, 22.91 eq). The mixture was stirred at 30°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with DCM (10 mL) and the resulting mixture was adjusted to pH about 8 with TEA. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether/ethyl acetate = 30/1, 5/1) to give 4-bromo-6-fluoro-5-isopropyl- 1H-Indazole (0.2 g, 777.90 umol, 88.48% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.11 (d, J=11.2 Hz, 1H), 3.75-3.63 (m, 1H), 1.38 (dd, J=1.7, 7.1 Hz, 6H).

Intermediate 1Q. 4-Bromo-6-fluoro-5-methoxy-1H-indazole

Step 1) 2-Bromo-4-fluoro-3-methoxy-1-methylbenzene

To a solution of 2-bromo-6-fluoro-3-methylphenol (4.8g, 23.41mmol, 1eq) in acetone (50mL) was added K2CO3 ( _6.47g , _46.82mmol , 2eq) and iodomethane (9.97g) , 70.24 mmol, 4.37 mL, 3 eq), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a residue. The residue was dissolved in ethyl acetate (50 mL), and the mixture was filtered, and the filtrate was concentrated to give the residue as a yellow oil (4.6 g, 21.00 mmol, 89.70% yield).

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.05-6.85 (m, 2H), 3.95 (d, J=1.2 Hz, 3H), 2.38 (s, 3H).

Step 2) 3-Bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene

To a solution of 2-bromo-4-fluoro-3-methoxy-1-methylbenzene (4.4 g, 20.09 mmol, ₁ eq) in _H2SO4 (40 mL) (98%) was added portionwise at 0 °C _KNO3 (2.23 g, 22.10 mmol, 1.1 eq) and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was slowly poured into ice water (200 mL), then the mixture was extracted with ethyl acetate (200 mL*2), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. 3-Bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (4.6 g, crude) was obtained as a brown oil.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (d, J=10.9 Hz, 1H), 4.08 (d, J=2.7 Hz, 3H), 2.61 (d, J=1.1 Hz, 3H).

Step 3) 3-Bromo-5-fluoro-4-methoxy-2-methylaniline

To a solution of 3-bromo-1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (4.6 g, 17.42 mmol, 1 eq) in EtOH (30 mL) and _H2O (30 mL) was added Fe (5.84 g, 104.53 mmol, 6 eq) and NH ₄ Cl (5.59 g, 104.53 mmol, 6 eq), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to remove EtOH, then the mixture was diluted with EA (50 mL), and the mixture was washed with water (20 mL*2), then the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue . 3-Bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, crude) was obtained as a brown oil.

¹ H NMR(400MHz, CHLOROFORM-d)δ6.44(d,J=11.9Hz,1H),3.83(s,3H),3.76-3.48(m,2H),2.24(d,J=1.0Hz,3H) ).

Step 4) 4-Bromo-6-fluoro-5-methoxy-1H-indazole

To a mixture of 3-bromo-5-fluoro-4-methoxy-2-methylaniline (3.5 g, 14.95 mmol, 1 eq) (crude) in AcOH (20 mL) at 0 °C was added NaNO ₂ (1.24 g) dropwise g, 17.94 mmol, 1.2 eq) in _H2O (4 mL), then the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ice water (100 mL), and the mixture was adjusted to pH 7 by using KOH, then the mixture was extracted with EA (100 mL*2), the combined organic layers were washed with brine (50 mL*2), washed with Na ₂ SO ₄ Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=20/1-15:1). 4-Bromo-6-fluoro-5-methoxy-lH-indazole (600 mg, 2.45 mmol, 16.37% yield) was obtained as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.44 (br s, 1H), 8.00 (s, 1H), 7.52 (br d, J=10.4 Hz, 1H), 3.84 (s, 3H).

Synthesis of compounds of formula (I)

The following compounds were prepared using Synthetic Methods A-F. Illustrative synthetic examples of some compounds of the present disclosure are described below, and other compounds may be prepared by methods analogous to those described below using different starting or reaction materials.

Synthetic method A

Example 1(1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl) Cyclopropane-1-carboxamide

Step 1) Methyl 5-amino-1-(3-methoxy-3-oxoprop-1-en-1-yl)-1H-pyrazole-3-carboxylate

To a solution of compound 1 (9.1 g, 64.48 mmol, 1 eq) in EtOH (700 mL) was added methyl propiolate (27.11 g, 322.40 mmol, 26.84 mL, 5 eq). The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure until all solids precipitated, filtered and concentrated under reduced pressure to give crude product. Compound 2 (7.8 g, crude) was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.09(d,J=14.8Hz,1H),7.05(s,1H),6.68(br s,2H),6.63(d,J=14.8Hz,1H) ), 3.88(s, 3H), 3.76(s, 3H).

Step 2) Ethyl 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate

To compound 2 (3.9 g, 17.32 mmol, 1 eq) in EtOH (15 mL) was added EtONa (1.77 g, 25.98 mmol, 1.5 eq). The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water 200 mL and extracted with ethyl acetate (200 mL*2). The aqueous layer was filtered, and the resulting filter cake was concentrated under reduced pressure to give compound 3 (5.4 g, crude) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ12.62(br s,1H),7.99(d,J=7.5Hz,1H),6.58(s,1H),5.82(d,J=7.5Hz,1H) ), 4.35 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).

Step 3) Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate

To a solution of compound 3 (1 g, 4.83 mmol, 1 eq) in MeCN ( ₅ mL) under N atmosphere was added N,N-dimethylaniline (1.17 g, 9.65 mmol, 1.22 mL, 2 eq), benzyl chloride (Triethyl)ammonium (5.50 g, 24.13 mmol, 5 eq) and _POCl3 (7.40 g, 48.27 mmol, 4.49 mL, 10 eq). The reaction mixture was stirred at 100 °C for 16 h under _N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was quenched with water (100 mL) and treated with saturated sodium bicarbonate solution until pH=7. The mixture was then extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine 100 mL, dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0-1:1). Compound 4 was obtained as a yellow solid (900 mg, 3.99 mmol, 82.64% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.63 (d, J=4.5Hz, 1H), 7.61 (d, J=4.5Hz, 1H), 7.36 (s, 1H), 4.40 (d, J= 7.1Hz, 2H), 1.36 (t, J=7.1Hz, 3H).

Step 4) Ethyl 5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate

Under _N2 atmosphere, compound 4 (900 mg, 3.99 mmol, 1 eq), (5-methyl-1H-indazol-4-yl)boronic acid (701.95 mg, 3.99 mmol, ₁ eq) and _Na2CO3 (845.55 mg, 7.98 mmol, 2 eq) in dioxane (5 mL) and H ₂ O (1 mL) was added Pd(dppf)Cl ₂ (145.93 mg, 199.44 umol, 0.05 eq). The mixture was stirred at 80 °C for 16 h under _N2 atmosphere. The reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0-0:1). Compound 5 was obtained as a yellow solid (450 mg, 1.40 mmol, 35.10% yield).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.28(s, 1H), 8.81-8.78(m, 1H), 7.71(d, J=8.5Hz, 1H), 7.66(s, 1H), 7.44( d, J=8.5Hz, 1H), 7.34(d, J=4.1Hz, 1H), 7.31(s, 1H), 4.30(q, J=7.1Hz, 2H), 2.14(s, 3H), 1.27( t, J=7.1 Hz, 3H).

Step 5) 5-(5-Methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid

To a solution of compound 5 (450 mg, 1.40 mmol, 1 eq) in THF (5 mL) and H ₂ O (5 mL) was added LiOH·H ₂ O (117.53 mg, 2.80 mmol, 2 eq). The mixture was stirred at 45°C for 2 hours. The reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (100 mL*2). The combined aqueous layers were treated with HCl (1 M) until pH 4, stirred until all solids precipitated, filtered and concentrated under reduced pressure to give a residue. Compound 6 (330 mg, crude) was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.51-13.06 (m, 1H), 8.77 (d, J=4.2 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.66 (d, J=0.9Hz, 1H), 7.43 (d, J=8.7Hz, 1H), 7.31 (d, J=4.2Hz, 1H), 7.24 (s, 1H), 2.14 (s, 3H).

Step 6) 5-(5-Methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine

To a solution of compound 6 (230 mg, 784.23 umol, 1 eq) in toluene ( ₂ mL) under N atmosphere was added TEA (87.29 mg, 862.66 umol, 120.07 uL, 1.1 eq) and DPPA (237.40 mg, 862.66 umol, 186.93 uL) , 1.1eq). The mixture was stirred at 110°C for 16 hours. Under _N2 atmosphere, _H2O (1.00 g, 55.51 mmol, 1 mL, 70.78 eq) was added to the mixture. The mixture was stirred at 110 °C for 3 h under _N2 atmosphere. The reaction mixture was diluted with water 50 mL and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=0:1). Compound 7 was obtained as a yellow solid (70 mg, 264.87 umol, 33.77% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ13.19(s, 1H), 8.32(d, J=4.3Hz, 1H), 7.63-7.59(m, 2H), 7.35(d, J=8.6Hz, 1H), 6.71 (d, J=4.4Hz, 1H), 5.79 (s, 1H), 5.71-5.63 (m, 2H), 2.15 (s, 3H).

Step 7) (1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)ring Propane-1-carboxamide

To compound 7 (70 mg, 264.87 umol, 1 eq), (1S,2S)-2-fluorocyclopropanecarboxylic acid (33.08 mg, 317.84 umol, 1.2 eq) and 3-methyl methanoic acid (33.08 mg, 317.84 umol, _1.2 eq) under N atmosphere at 0 °C To a solution of pyridine (123.33 mg, 1.32 mmol, 128.95 uL, 5 eq) in MeCN (2 mL) was added MsCl (45.51 mg, 397.30 umol, 30.75 uL, 1.5 eq). The mixture was stirred at 25 °C for 16 h under _N2 atmosphere. The reaction mixture was added dropwise to water 20 mL and extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine 20 mL, dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=0:1). The residue was then purified by prep-HPLC (column: Phenomenex lunaC18150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: %-%, 10 minutes) and lyophilized. Example 1 (4.3 mg, 12.27 umol, 4.63% yield, 100% purity) was obtained as a yellow solid.

¹ H NMR (400MHz, METHANOL-d ₄ )δ8.57(d,J=4.3Hz,1H),7.66(d,J=8.6Hz,1H),7.64(d,J=2.3Hz,1H),7.44 (d, J=8.8Hz, 1H), 7.13(s, 1H), 7.04(d, J=4.3Hz, 1H), 4.75-4.61(m, 1H), 2.26(s, 3H), 1.98-1.90( m, 1H), 1.83-1.72 (m, 1H), 1.19-1.11 (m, 1H).

Synthetic method B

Example 3 (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl) Cyclopropane-1-carboxamide

Step 1) N-(6-Chloropyridazin-3-yl)-4-methylbenzenesulfonamide

To a solution of compound 8 (25 g, 192.98 mmol, 1 eq) in pyridine (300 mL) was added TsCl (40.47 g, 212.28 mmol, 1.1 eq), then the mixture was stirred at 90 °C under N ₂ for 6 h. Water (100 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (50 mL*3), then the organic phase was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under vacuum to obtain a grey solid. Compound 9 (56.5 g, crude).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.67-8.59(m,1H),7.82-7.77(m,2H),7.61-7.54(m,1H),7.52-7.46(m,1H),7.38 (d, J=8.3 Hz, 2H), 2.35 (s, 3H).

Step 2) (E)-2-(3-Chloro-6-(tosylimido)pyridazin-1(6H)-yl)acetamide

To a solution of compound 9 (53g, 186.79mmol, 1eq) in DMF (300mL) was added DIPEA (26.56g, 205.47mmol, 35.79mL, 1.1eq) and 2-bromoacetamide (28.35g, 205.47mmol, 1.1eq), The mixture was then stirred at 25°C for 20 hours. To the mixture was added water (1000 mL) and the mixture was filtered, the filter cake was collected and concentrated in vacuo to give compound 10 (40 g, 117.38 mmol, 62.84% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (d, J=9.8 Hz, 1H), 7.79 (d, J=9.8 Hz, 1H), 7.70 (brd, J=7.1 Hz, 3H), 7.38 (br s, 1H), 7.32 (br d, J=7.8Hz, 2H), 4.88-4.77 (m, 2H), 2.40-2.30 (m, 3H).

Step 3) N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2,2,2-trifluoroacetamide

To a solution of compound 10 (35 g, 102.70 mmol, 1 eq) in DCE (250 mL) was added TFAA (258.85 g, 1.23 mol, 171.43 mL, 12 eq), and the mixture was stirred at 60°C for 3 hours. Water (1000 mL) was added to the mixture, then sufficient NaHCO was added to the mixture to adjust the pH to ₈ , then the mixture was filtered and the filter cake was collected, then extracted with water (500 mL) and ethyl acetate (500 mL), then The organic phase was dried _{over Na2SO4} and concentrated in vacuo to obtain compound 11 (21 g, 79.37 mmol, 77.28% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ12.88-12.57(m,1H),8.41(s,1H),8.19(d,J=9.4Hz,1H),7.43(d,J=9.4Hz, 1H).

Step 4) 6-chloroimidazo[1,2-b]pyridazin-2-amine

To a solution of compound 11 (21 g, 79.37 mmol, 1 eq) in MeOH (200 mL) and H ₂ O (200 mL) was added K ₂ CO ₃ (54.85 g, 396.84 mmol, 5 eq), and the mixture was stirred at 75 °C for 3 Hour. Water (100 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (50 mL*3), then the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to obtain compound 60 (13.5 g, crude).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.68(d, J=9.2Hz, 1H), 7.36(s, 1H), 7.03(d, J=9.2Hz, 1H), 5.65(s, 2H) .

Step 5) (1S,2S)-N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide

To a solution of compound 12 (2 g, 11.86 mmol, 1 eq), (1S,2S)-2-fluorocyclopropanecarboxylic acid (1.56 g, 14.24 mmol, 1.2 eq) in DCM (50 mL) was added EDCI (3.41 g, 17.80 mmol) , 1.5eq), then the mixture was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo to give a residue. Water (100 mL) was then poured into the mixture, and the mixture was extracted with ethyl acetate (50 mL*3), then the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give compound 13 (3.8 g) as a white solid ,Crude).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.37-11.22 (m, 1H), 8.32-8.23 (m, 1H), 8.07 (d, J=9.4Hz, 1H), 7.72-7.64 (m, 1H) ), 5.07-4.80 (m, 1H), 2.21-2.12 (m, 1H), 1.73-1.61 (m, 1H), 1.13-1.05 (m, 1H).

Step 6) (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl) ring Propane-1-carboxamide. 2TFA

To a solution of compound 13 (170 mg, 667.59 umol, 1 eq), Na ₂ CO ₃ (141.51 mg, 1.34 mmol, 2 eq) in dioxane (6 mL) and H ₂ O (2 mL) was added (5-methyl-1H) -Indazol-4-yl)boronic acid (117.48 mg, 667.59 umol, 1 eq) and Pd(dppf)Cl ₂ (48.85 mg, 66.76 umol, 0.1 eq), then the mixture was stirred at 90 °C under N ₂ for 16 h . The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 19%-49%, 10 minutes) to obtain pale yellow color Example 3 as a solid (56.8 mg, 93.88 umol, 14.06% yield, 95.6% purity, 2TFA).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.27 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=9.3Hz, 1H), 7.84 (d, J=0.9Hz, 1H) ,7.58(d,J＝8.4Hz,1H),7.38(dd,J＝8.9,16.1Hz,2H),5.08-4.82(m,1H),2.38(s,3H),2.23-2.14(m,1H) ), 1.77-1.62 (m, 1H), 1.23-1.12 (m, 1H).

Synthetic method C

Example 24 (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base) cyclopropanecarboxamide. 2TFA

Step 1) (1S,2S)-N-(6-bromoimidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropanecarboxamide

To a solution of (1S,2S)-2-fluorocyclopropanecarboxylic acid (537.41 mg, 5.16 mmol, 1.1 eq) and compound 14 (1 g, 4.69 mmol, 1 eq) in NMP (20 mL) was added T ₃ P (2.99 g, 9.39 mmol, 2.79 mL, 2 eq) and DIPEA (1.42 g, 11.03 mmol, 1.92 mL, 2.35 eq). The reaction mixture was stirred at 25°C for 16 hours. Water (15 mL) was added and the aqueous phase was extracted with EtOAc (10 mL*2). The combined organic phases were washed with saturated brine (10 mL*2) and concentrated in vacuo. The crude product was purified by reverse flash (MeCN/ _H2O . 0.05% TFA) to give compound 15 (750 mg, 2.51 mmol, 53.42% yield) as a pale yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.39(s, 1H), 8.93(d, J=1.2Hz, 1H), 8.75(s, 1H), 8.29(s, 1H), 5.17-4.76( m, 1H), 2.23-2.11 (m, 1H), 1.67 (tdd, J=3.3, 6.9, 19.9Hz, 1H), 1.25-1.13 (m, 1H).

Step 2) (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)ring Propylformamide. 2TFA

To a solution of (5-methyl-1H-indazol-4-yl)boronic acid (58.84 mg, 334.34 umol, 1 eq) in dioxane/H ₂ O (3 mL) under N ₂ was added Pd(dppf) Cl ₂ (12.23 mg, 16.72 umol, 0.05 eq), compound 15 (100 mg, 334.34 umol, 1 eq) and Na ₂ CO ₃ (70.87 mg, 668.67 umol, 2 eq). The mixture was stirred at 90°C for 3 hours. Water (10 mL) was added and the aqueous phase was extracted with EtOAc (10 mL*2). The combined organic phases were washed with saturated brine (10 mL*2) and concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 13%-43%, 10 minutes) to give light yellow color Example 24 as a solid (38.2 mg, 62.74 umol, 18.77% yield, 95% purity, 2TFA).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.48-11.28(m, 1H), 9.06(s, 1H), 8.83(d, J=1.3Hz, 1H), 8.36(s, 1H), 7.91( d,J＝0.9Hz,1H),7.52(d,J＝8.3Hz,1H),7.33(d,J＝8.6Hz,1H),5.15-4.79(m,1H),2.43-2.35(m,3H) ), 2.26-2.14 (m, 1H), 1.78-1.62 (m, 1H), 1.37-1.06 (m, 1H).

Synthetic method D

Example 25 (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- yl)-2-fluorocyclopropanecarboxamide. 2TFA

Step 1) (1S,2S)-2-Fluoro-N-(6-(tributylstannyl)imidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide.

To a solution of tributyl(tributylstannyl)stannane (1.16 g, 2.01 mmol, 1.00 mL, 3 eq) and compound 16 (200 mg, 668.67 umol, 1 eq) in dioxane (3 mL) under _N2 Pd(PPh ₃ ) ₄ (38.63 mg, 33.43 umol, 0.05 eq) and TBAI (246.99 mg, 668.67 umol, 1 eq) were added. The reaction mixture was stirred at 110°C for 32 hours. The reaction was filtered and the filtrate was concentrated to give the product. The crude product was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to give compound 17 (130 mg, 255.28 umol, 38.18% yield) as a white solid.

Step 2) (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)- 2-Fluorocyclopropanecarboxamide. 2TFA

To a solution of 4-bromo- ₅ -ethyl-6-fluoro-1H-indazole (40 mg, 164.56 umol, 1 eq) and compound 17 (92.18 mg, 181.01 umol, 1.1 eq) in EtOH (2 mL) under N2 Ad2n _- BuP-Pd-G3 (11.98 mg, 16.46 umol, 0.1 eq) was added to it. The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 24%-54%, 10 minutes) to give a white solid of Example 25 (10 mg, 16.22 umol, 9.86% yield, 99% purity, 2TFA).

¹ H NMR(400MHz METHANOL-d ₄ )δ8.99(s,1H),8.71(s,1H),8.42(s,1H),7.83(s,1H),7.36(d,J=10.4Hz,1H ), 5.00-4.97(m, 1H), 2.76-2.72(m, 2H), 2.16-2.15(m, 1H), 1.86-1.79(m, 1H), 1.26-1.24(m, 1H), 1.19-1.16 (m, 3H).

Synthetic Method E

Example 61 (1S,2S)-N-(6-(5-chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide

To a solution of compound 17 (456 mg, 0.896 mmol, 1.3 eq) and intermediate 1E (269 mg, 0.689 mmol) in EtOH (3.44 mL) was added Ad2nBuP _- Pd-G3 (50 mg, 0.0689 mmol, 0.1 eq). The mixture was degassed and purged with N ₃ times, then stirred at 90 °C for ₁₆ h under a N atmosphere. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (product appeared in ethyl acetate) to provide Example 61 (86 mg, 0.162 mmol, 24% yield) as a yellow solid.

Synthetic method F

Example 64 (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a] pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide

Step 1) 4-Bromo-5-chloro-6-fluoro-7-(prop-1-en-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

To intermediate 1B (2 g, 4.35 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en- ₂ -yl)-1,3,2 under N atmosphere - To a solution of dioxaborane (877.73 mg, 5.22 mmol, 1.2 eq) in dioxane (0.4 mL) and H ₂ O (0.1 mL) was added Na ₂ CO ₃ (922.69 mg, 8.71 mmol, 2 eq) and Pd (dppf)Cl ₂ (159.25 mg, 217.64 μmol, 0.05 eq). The mixture was stirred at 80 °C for 16 h under _N2 atmosphere. The reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine 100 mL, dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0-20:1). Compound 18 was obtained as a yellow oil (870 mg, 2.33 mmol, 53.49% yield).

Step 2) 4-Bromo-5-chloro-6-fluoro-7-isopropyl-1H-indazole

To a solution of compound 18 (400 mg, 1.07 mmol, 1 eq) in MeOH (0.5 mL) under N ₂ was added PtO ₂ (40.00 mg, 176.15 umol, 1.65e-1 eq). The suspension was degassed under vacuum and purged with _H2 several times. The mixture was stirred under _H2 (15 psi) at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0-4:1). Compound 19 was obtained as a yellow solid (240 mg, 823.19 umol, 76.90% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.73 (br s, 1H), 8.09 (s, 1H), 3.59-3.49 (m, 1H), 1.39 (d, J=6.9 Hz, 6H).

Step 3) (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide

To a solution of compound 19 (70 mg, 240.10 umol, 1 eq), compound 17 (134.50 mg, 264.11 umol, 1.1 eq) in EtOH (1 mL) under N atmosphere was added Ad ₂ nBuP-Pd-G3 (17.49 mg, 24.01 mg ₎ umol, 0.1eq). The mixture was stirred at 80 °C for 12 h under _N2 atmosphere. 5 mL of saturated aqueous KF solution was added to quench the reaction mixture. The mixture was dissolved in water (20 mL) and extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine 20 mL, dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-60%, 10 minutes) and lyophilized. Example 64 was obtained as a white solid (15 mg, 34.12 umol, 14.21% yield, 98% purity).

¹ H NMR (400MHz, DMSO-d ₆ )δ13.52(br s,1H),11.40(s,1H),9.14-8.87(m,2H),8.38(s,1H),8.04(br s,1H) ), 5.17-4.75(m, 1H), 3.66-3.59(m, 1H), 2.19(td, J=7.0, 13.6Hz, 1H), 1.75-1.62(m, 1H), 1.45(br d, J= 7.0 Hz, 6H), 1.20 (tdd, J=6.3, 8.9, 12.3 Hz, 1 H); LCMS (electrospray) m/z 431.2 (M+H+).

Table 1 below shows the compounds of the examples and the general synthetic methods and characterization data used to prepare the compounds.

Table 1. Compounds of the Examples

Evaluation of compounds

HPK1 kinase assay

HPK1 kinase activity was measured by Promega's ADP-Glo ^™ Kinase Assay. In this assay, 5 ng of recombinant human HPK1 (signalchem) was combined with 5 μL of compound (0.5% DMSO), 5 μL of MBP (0.5 μg/μl) and 5 μL of ATP (25 μM) buffer (40 mM Tris, 7.5; 20 mM MgCl) ₂ ; 0.1 mg/ml BSA; 50 μM DTT.) were incubated together. Assays were initiated by incubating the reaction mixture in a 96-well plate at 30°C for 40 minutes. After incubation, 25uL of ADP-Glo reagent was added and the reaction was incubated at room temperature for 40 minutes to stop the reaction and degrade residual ATP. The ADP product was then converted to ATP by adding 50 uL of detection reagent to each well. Luminescence was detected after 30 min incubation at room temperature with a Molecular device 13X plate reader. _IC50 values were calculated from a range of percent inhibition values determined over a range of inhibitor concentrations using GraphPad Prism 7 software and a software program implemented in SigmaPlot 13.0.

Table 2 shows the _IC50 values for compounds of the invention, where + is represented as >1000 nM, ++ is 501-1000 nM, +++ is 101-500 nM, and ++++ is <100 nM.

Table 2. In vitro activity against HPK1 data

IFNγ and IL-2 analysis of human peripheral pan-T cells

Human peripheral blood pan-T cells were purchased from STEMCELL ^™ Technologies Inc. Human peripheral blood pan-T cells were thawed and suspended in DMEM medium (10% FBS and 1% penicillin/streptomycin). 8X10 ⁴ T cells were seeded in 96-well plates and incubated with various concentrations of compounds and 100 nM prostaglandin E2 for 1 hour. T cells were stimulated with Dynabeads human T-activator CD3/CD28 (Life Technologies) at a cell:bead ratio of 1:3. Cytokine secretion was measured 24 h post-stimulation using the MSD V-PLEX Human Cytokine Kit following the manufacturer's recommendations. Data were analyzed with MESO Quickplex SQ120 (Mesoscale Discovery).

In Table 3, the value + is indicated as >1000 nM, ++ is 200-1,000 nM, +++ is <200 nM and - is not determined.

Table 3. IFNγ and IL-2 secretion of compounds of the present invention in human peripheral blood pan-T cells

Claims (29)

1. A compound of formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: X is O or S; L is a bond, -O-, -S- or -NR ⁶ -; R1 is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein R1 is optionally substituted with ^one or more substituents independently selected from ^{R7 ;} R ⁶ is -H or C _1-6 alkyl; R ⁷ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, oxo, cyano, hydroxyl, - C(O)R ⁹ , -C(O)OR ⁹ , -C(O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -SR ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N( R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ , -N(R ⁶ )C (O)NR ¹⁰ R ¹¹ , -N(R ⁶ )S(O) ₂ R ⁹ , -N(R ⁶ )S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ ; R ⁹ is -H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; Each R ¹⁰ and R ¹¹ is independently -H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclic group optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, Haloalkyl, hydroxyalkyl, -CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(= O)OR ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(=O)R ⁹ , -OC( =O) OR ⁹ and the group consisting of -OC(=O)NR ¹⁰ R ¹¹ ; Each of R ¹² and R ¹³ is independently C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, or R ¹² and R ¹³ Together with the phosphorus atom to which they are attached form a 4-8 membered heterocyclic group optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkane base, -CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)OR ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(=O)R ⁹ , -OC(=O)OR ⁹ and the group consisting of -OC(=O)NR ¹⁰ R ¹¹ ; Het is selected from the group consisting of:

R ^a , R ^b and R ^c are each independently -H, -D, halogen, -CF ₃ , -CF ₂ H, -CH ₂ F, -CN, -OR ⁹ or -NR ¹⁰ R ¹¹ ; R ² is -H, -D, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen , hydroxyl, -CD ₂ OH, -CN, -NO ₂ , haloalkyl, trimethylsilylethoxymethyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O )NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -SR ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , - S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N (R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ , -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ , -N(R ⁶ )S(O) ₂ R ⁹ , -N(R ⁶ )S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ , wherein C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, alkane group, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)OR ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(= ^The group consisting of O) ^R9 , -OC(=O) ^OR9 and -OC(=O) ^NR10R11 ; R ³ is -H, -D, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen substituted, cyano, hydroxyl, -CH ₂ OH, -CD ₂ OH, -OH, -CN, -NO ₂ , haloalkyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O )NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -SR ⁹ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , - S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N(R ⁶ )OR ⁹ , -N (R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ , -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ , -N(R ⁶ )S(O) ₂ R ⁹ , -N(R ⁶ )S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ ; M is a bond, -O-, -S- or -NR ⁶ -; R ⁶ is -H or C _1-6 alkyl; R ⁴ is -H, -D, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, Hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C(O)NR ¹⁰ R ¹¹ , -S(O) ₂ R ⁹ , -S(O)(=NH)R ¹⁰ , -S(O) ₂ NR ¹⁰ R ¹¹ or -P(O)R ¹² R ¹³ , wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl , heteroaryl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -CN, -CD ₃ , -NO ₂ , -NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)R ⁹ , -NR ¹⁰ C(=O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(=O)OR ⁹ , -NR ¹⁰ S (O) ₂ R ⁹ , -OR ⁹ , -C(=O)R ⁹ , -C(=O)OR ⁹ , -C(=O)NR ¹⁰ R ¹¹ , -OC(=O)R ⁹ , - the group consisting of OC(=O) ^OR9 and -OC(=O) ^{NR10R11 ;} and R ⁵ is -H, -D, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, hydroxyl, -CH ₂ OH, -CD ₂ OH, -CN or haloalkyl. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond, and R1 is ^a cycloalkyl, optionally substituted with one or more groups selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C (O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N( The group consisting of R ⁶ )OR ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ and -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ . 3. The compound of claim ¹ , or a pharmaceutically acceptable salt thereof, wherein R2 and ^R3 are each independently -H, halogen, alkylthio, haloalkyl, or alkyl. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is a bond, -O- or -NR ⁶ -; and R ⁴ is -H, -D, C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O) NR ¹⁰ R ¹¹ , -S(O) ₂ R ⁹ , -S(O)(=NH)R ¹⁰ or -S(O) ₂ NR ¹⁰ R ¹¹ , wherein, C _1-6 alkyl, C _2-6 Alkenyl, _C2-6alkynyl , cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, alkenyl, ^The group consisting of alkynyl, haloalkyl, hydroxyalkyl, ^-CN , ^-CD3 , _-NR10R11 , ^-NR10S (O) _2R9 and ^-NR10C (=O) ^R9 . 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II):

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L is a bond; R ¹ is cyclopropyl, optionally substituted by one or more groups selected from halogen , C _1-3 alkyl, C _1-3 hydroxyalkyl and C _1-3 haloalkyl groups; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, Alkyl or halogen; M is a bond, -O-, -S- or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyano alkyl, aminocarbonyl alkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxy ring Alkyl, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutylcarbonylaminoethyl, dioxanyl Fluoroacetamidoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1 ,1,1,3,3,3-d6) amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrrolidyl azolyl or methylpyrazolylmethyl; and R ⁵ is -H, alkyl or halo. 7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, which is (1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)cyclopropane-1 - formamide; or (1S,2S)-N-(5-(5-ethyl-6,7-difluoro-1H-indazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)- 2-Fluorocyclopropane-1-carboxamide. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III):

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R1 is cycloalkyl, optionally substituted with ^one or more groups selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C (O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N( The group consisting of R ⁶ )OR ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ and -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ . 10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C _1- The group consisting of ₃ alkyl, C _1-3 hydroxyalkyl and C _1-3 haloalkyl; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkyl or halogen ; M is a bond, -O-, -S- or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyanoalkyl, Aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkyl, cycloalkyl Alkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutylcarbonylaminoethyl, difluoroacetamidoethyl base, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1,1,1 ,3,3,3-d6) amino, tetrahydrofuranyl, methylimidazolylethyl, furanyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazolyl or methyl and R ⁵ is -H, alkyl or halogen. 11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)cyclopropane-1 - formamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluoro cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl) cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)- 2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-Difluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)- 2-Fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2 - base) cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocycle Propane-1-carboxamide; (1S,2S)-N-(6-(5-Amino-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluorocycle Propane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b ]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-ethoxy-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b] Pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-b ]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-Difluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2 - Fluorocyclopropane-1-carboxamide; and (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2 -yl)-2-fluorocyclopropane-1-carboxamide. 12. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-2-fluoro cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b ]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-b ]pyridazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; and (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-b]pyridazine-2 -yl)-2-fluorocyclopropane-1-carboxamide. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV):

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein L is a bond, and R1 is cycloalkyl, optionally substituted with ^one or more groups selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, halogen, cyano, hydroxyl, -C(O)R ⁹ , -C(O)OR ⁹ , -C (O)NR ¹⁰ R ¹¹ , -OR ⁹ , -OC(O)R ⁹ , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ R ¹¹ , -N(R ⁶ )NR ¹⁰ R ¹¹ , -N( The group consisting of R ⁶ )OR ⁹ , -N(R ⁶ )C(O)R ⁹ , -N(R ⁶ )C(O)OR ⁹ and -N(R ⁶ )C(O)NR ¹⁰ R ¹¹ . 15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein L is a bond; R is cycloalkyl, optionally substituted with ^one or more groups selected from halogen , C _1-3 alkyl, C _1-3 hydroxyalkyl and C _1-3 haloalkyl group. 16. The compound of claim 13, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1 - formamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluoro cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5,7-bis(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 - base) cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)- 2-Fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-methyl-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl) cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocycle Propane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-ethoxy-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-Difluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)- 2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6,7-Difluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(Dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-methyl-7-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Bromo-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2 - Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6,7-difluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2 - Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Bromo-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocycle Propane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(pyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(piperidin-1-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((3-hydroxypropyl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(azetidin-1-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-thiomorpholin-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isopropyl(methyl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-1-en-2-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1-cyanoethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1H-pyrrol-1-yl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-Amino-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)- 2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((cyanomethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((2H-tetrazol-2-yl)methyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-hydroxypropan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-vinyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl) -2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-Acetyl-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl) -2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-cyclopropyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(2-ethoxypropan-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(tert-butylamino)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-fluoropyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methyl-1H-pyrrol-2-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-1-yn-1-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-methyl-7-(prop-1-en-2-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-propyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl) -2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methyl-1H-pyrrol-1-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; 1-(5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl )-1H-indazol-7-yl)-N,N-dimethyl-1H-pyrrole-3-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxypropan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-fluoropropan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isobutylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(propylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((E)-prop-1-en-1-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(ethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (3R,4S)-4-Methyltetrahydrofuran-3-yl(6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)carbamate; (1S,2S)-N-(6-(5-Chloro-7-(2-(dimethylamino)-2-oxoethyl)-6-fluoro-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((2-(dimethylamino)-2-oxoethyl)thio)-6-fluoro-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-fluoroethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((methylamino)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((dimethylamino)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(prop-1-en-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methyl-1H-pyrrol-3-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1H-pyrrol-3-yl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methyl-1H-pyrazol-5-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((1-hydroxy-2-methylpropan-2-yl)amino)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-tert-pentanoyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-cyclopropoxy-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; 4-Methyltetrahydrofuran-3-yl(6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl) carbamate; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-hydroxyethyl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclobutylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopentylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-methoxyethyl)amino)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1,1,1-trifluoropropan-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((1-hydroxypropan-2-yl)amino)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((1-methoxypropan-2-yl)amino)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R,3S)-N-(6-(5-Chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide; (1S,2S,3S)-N-(6-(5-Chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-fluoropropan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopent-1-en-1-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-imidazol-1-yl)methyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(morpholino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(2-Amino-2-oxoethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methylprop-1-en-1-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((2,2-difluoroethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(2-Bromo-2-fluorocyclopropyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(allylamino)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-cyclopentyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((4-methylpiperazin-1-yl)amino)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-fluoroethyl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-6-fluoro-1H-indazole-4 -yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl ) cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((1-methyl-1H-pyrazol-5-yl)amino)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((4-hydroxybutan-2-yl)amino)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2R,3S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide; (1S,2S,3S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-pyrrol-1-yl)methyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-pyrazol-1-yl)methyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(pyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-hydroxypyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((R)-3-hydroxypyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-oxocyclopent-1-en-1-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methoxyethyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(N-methylacetamido)ethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropyl(hydroxy)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((1H-pyrazol-5-yl)amino)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methyl(1H-pyrazol-5-yl)amino)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyridine oxazol-5-yl)amino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methyl(1-methyl-1H-pyrazol-5-yl)amino)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isobutyryl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxy-2-methylpropyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(((1S,3R)-3-hydroxycyclopentyl)amino)-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-methyl-1H-imidazol-1-yl)methyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxycyclopentyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,1-difluoropropan-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isobutyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methoxy-2-methylpropyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-fluoro-2-methylpropyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((4-methoxybutan-2-yl)amino)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((3-fluorocyclobutyl)amino)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropyl(methoxy)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((E)-but-2-en-2-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(but-3-en-2-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butylamino)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-methyl-1H-pyrrol-1-yl)methyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((4-methyl-1H-imidazol-1-yl)methyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((4-methyl-1H-pyrazol-1-yl)methyl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((S)-3-hydroxypyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-hydroxycyclopentyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((tetrahydrofuran-3-yl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methoxycyclopentyl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(((1S,3S)-3-hydroxycyclopentyl)amino)-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-(dimethylamino)-1-oxopropan-2-yl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((S)-1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-cyanoethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(1H-tetrazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((S)-1-(1H-tetrazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-Amino-1-oxopropan-2-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((1-fluoropropan-2-yl)amino)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(furan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isoxazol-4-yl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(((1R,3S)-3-hydroxycyclopentyl)amino)-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-hydroxycyclopentan-1-en-1-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((3-methyl-1H-pyrazol-1-yl)methyl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methyl(tetrahydrofuran-3-yl)amino)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(2H-1,2,3-triazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole- 4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1-(1H-1,2,4-triazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole- 4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methoxypyrrolidin-1-yl)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((R)-3-methoxypyrrolidin-1-yl)-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((S)-3-methoxypyrrolidin-1-yl)-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1-cyclopropylethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((3,3-difluorocyclobutyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxyprop-2-yn-1-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-Acetylaminoethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(2-cyanopropan-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(5-methylfuran-2-yl)-2H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-(methylthio)-7-(prop-1-en-2-yl)-1H-indazol-4-yl) ) imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((E)-butane-1,3-dien-1-yl)-5-chloro-6-fluoro-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((S)-1,1,1-trifluoropropan-2-yl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((R)-1,1,1-trifluoropropan-2-yl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((cyclopropylmethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((R)-1-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((S)-1-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-ethoxy-2,2,2-trifluoroethyl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1,2,2,2-tetrafluoroethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((3S,4S)-3,4-dimethoxypyrrolidin-1-yl)-6-fluoro-1H-indazole- 4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(furan-3-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-1,2-dien-1-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(hydroxy(tetrahydro-2H-pyran-3-yl)methyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-(methylthio)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(5,6-dihydro-1,4-dioxin-2-yl)-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1H-pyrazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(((1R,3S)-3-hydroxycyclopentyl)(methyl)amino)-1H-indazole-4 -yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(prop-1-en-2-yl)-5-(trifluoromethyl)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(5-methylfuran-3-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-hydroxyprop-1-yn-1-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-2-yn-1-ylamino)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1,1-difluoropropan-2-yl)amino)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(4-hydroxytetrahydrofuran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(3,3-dimethylazetidin-1-yl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((3-chloro-2,2-dimethylpropyl)amino)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(4-methyl-1H-pyrazol-1-yl)ethyl)-1H-indazole-4 -yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(5-methyl-1H-pyrazol-1-yl)ethyl)-1H-indazole-4 -yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(3-methyl-1H-pyrazol-1-yl)ethyl)-1H-indazole-4 -yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(3,3-difluoroazetidin-1-yl)-6-fluoro-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyanomethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(2,5-dihydrofuran-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-propionamidoethyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-hydroxypropionamido)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-carboxamidoethyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((E)-4-hydroxybut-1-en-1-yl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbut-1-en-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbut-2-en-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-(trimethylsilyl)prop-2-yn-1-yl)-1H-indazole-4 -yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide. 1 formic acid; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxy-3-(trimethylsilyl)prop-2-yn-1-yl)-1H- indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((3-hydroxybutan-2-yl)amino)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(5,5-dimethyltetrahydrofuran-3-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1H-imidazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(2-methyl-1H-imidazol-1-yl)ethyl)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((E)-3-(triethylsilyl)prop-1-en-1-yl)-1H- indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1,1-difluoropropan-2-yl)(methyl)amino)-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,4-dioxan-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(tetrahydro-2H-pyran-3-yl)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(4-methyl-1H-imidazol-1-yl)ethyl)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyanofluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetylamino(cyano)methyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-fluoro-1H-indone oxazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(methylsulfonamido)ethyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,1-difluoroprop-1-en-2-yl)-6-fluoro-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1S,2R)-1,2-dihydroxypropyl)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-2-yn-1-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbutan-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbut-2-en-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetylaminomethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-formyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl) -2-Fluorocyclopropane-1-carboxamide; 5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl)-1H - ethyl indazole-7-carboxylate; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(((2R,3R)-3-methoxybutan-2-yl)(methyl)amino)-1H -Indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(((2R,3S)-3-methoxybutan-2-yl)(methyl)amino)-1H -Indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-((1-cyanocyclopropyl)amino)ethyl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-(5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl )-1H-indazol-7-yl)ethyl acetate; (9H-Fluoren-9-yl)methyl(5-chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2 -a]pyrazin-6-yl)-1H-indazol-7-yl)carbamate; (1S,2S)-N-(6-(5-Chloro-7-(difluoromethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(hydroxy)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(1-(5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazine- 6-yl)-1H-indazol-7-yl)ethyl)cyclobutanecarboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-fluorocyclopropyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(tetrahydrofuran-3-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((methylthio)methyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(methylthio)ethyl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((methylsulfinyl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((methylsulfonyl)methyl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,3-dimethylureido)-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1S,2R)-1,2-dimethoxypropyl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-(2,2-difluoroacetamido)ethyl)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methyl-1H-imidazol-5-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(methylsulfonyl)ethyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(methylsulfinyl)ethyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-(ethylamino)-1-oxopropan-2-yl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(2,2,2-trifluoroacetamido)methyl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-(5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazin-6-yl )-1H-indazol-7-yl)-3-(cyclobutylamino)-3-oxopropionic acid methyl ester; (1S,2S)-N-((5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a ]pyrazin-6-yl)-1H-indazol-7-yl)(cyano)methyl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(cyclopropionamido)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(2,2-difluoroacetamido)methyl)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((propan-2-yl-1,1,1,3,3,3-d6)amino)-1H-indium oxazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-6-fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; and (1S,2S)-N-(6-(5-ethoxy-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide. 17. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen , C ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl and C ₁ -C ₃ haloalkyl group; R ² is -H, alkyl, haloalkyl or halogen; R ³ is -H, alkane M is a bond, -O- or ^{-NR6- ;} R4 is -H, halogen, alkyl, monoalkylamino or dialkylamino ^; and R5 is -H, alkyl or halogen. 18. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein L is a bond; R ^a is -H; R ^b is -H; R ¹ is chloro, fluoro, C ₁ -C ₃ Alkyl, C ₁ -C ₃ hydroxyalkyl or C ₁ -C ₃ haloalkyl substituted cyclopropyl; R ² is -H, alkyl, chlorine or fluorine; R ³ is -H, alkyl, chlorine or fluorine M is a bond or -NH- ^; R4 is -H, chlorine, fluorine, methyl, ethyl, propyl, isopropyl, butyl, methylamino or dimethylamino ^; and R5 is -H or alkane base. 19. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein L is a bond; R ^a is -H; R ^b is -H; R ¹ is a cyclopropyl substituted by chlorine or fluorine; R ² is -H, chlorine or fluorine; R ³ is -H, chlorine or fluorine; M is a bond or -NH-; R ⁴ is -H, chlorine, fluorine, methyl, ethyl, propyl or isopropyl ^; and R5 is -H. 20. The compound of claim 17, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-Chloro-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2R)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; and (1R,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide. 21. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein L is a bond; R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen , C ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl and C ₁ -C ₃ haloalkyl groups; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkyl or halogen; M is a bond, -O-, -S- or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkane and R ⁵ is -H, alkyl or halo. 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S,2S)-N-(6-(5-Chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(Dimethylamino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-methyl-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-(methylthio)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)cyclopropane-1-carboxamide; and (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)cyclopropane-1-carboxamide. 23. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R ¹ is cyclopropyl, optionally substituted with one or more groups selected from halogen, C ₁ - The group consisting of C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl and C ₁ -C ₃ haloalkyl; R ² is -H, alkyl, halogen, haloalkyl or alkylthio; R ³ is -H, alkane group or halogen; M is a bond, -O-, -S- or -NR ⁶ -; R ⁴ is -H, halogen, alkyl, hydroxyalkyl, haloalkyl, haloalkenyl, cycloalkyl, cyano Alkyl, aminocarbonylalkyl, acetamidoethyl, propionamidoethyl, formamidoethyl, cycloalkylalkyl, cycloalkyl(hydroxy)alkyl, hydroxycycloalkyl, methoxycycloalkane group, cycloalkyl(methoxy)methyl, alkoxyalkyl, alkenyl, methylsulfonamidoethyl, imidazolylethyl, dioxanyl, cyclobutylcarbonylaminoethyl, difluoro Acetaminoethyl, trifluoroacetamidoethyl, methylthiomethyl, methylthioethyl, cyclopropylcarbonylamino(cyano)methyl, cyano(difluoroacetamido)methyl, propyl-1, 1,1,3,3,3-d6) amino, tetrahydrofuranyl, methylimidazolylethyl, furyl, pyrrolyl, methylpyrrolyl, isoxazolyl, tetrazolylalkyl, methylpyrazole and R ⁵ is -H, alkyl or halogen. 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S,2S)-N-(6-(7-(dimethylamino)-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine- 2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5,7-bis(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-ethoxy-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-7-(ethyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-ethoxy-5-ethyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(ethyl(methyl)amino)-6-fluoro-5-(methylthio)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isopropyl(methyl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-1-en-2-yl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1H-pyrrol-1-yl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((cyanomethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-cyclopropyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methyl-1H-pyrrol-2-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-methyl-7-(prop-1-en-2-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-propyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl) -2-Fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methyl-1H-pyrrol-1-yl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxypropan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-fluoropropan-2-yl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(propylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(ethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(prop-1-en-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethyl-6-fluoro-7-(isopropylamino)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-methyl-1H-pyrazol-5-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-cyclopropoxy-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclobutylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-methoxyethyl)amino)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1,1,1-trifluoropropan-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((1-hydroxypropan-2-yl)amino)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isopropoxy-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2- base)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methylprop-1-en-1-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((2,2-difluoroethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(allylamino)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-cyclopentyl-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((2-fluoroethyl)amino)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-(methylthio)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropyl(hydroxy)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(methyl(1-methyl-1H-pyrazol-5-yl)amino)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-hydroxy-2-methylpropyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-isopropyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,1-difluoropropan-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-isobutyl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl )-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-fluoro-2-methylpropyl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyclopropyl(methoxy)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((E)-but-2-en-2-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(but-3-en-2-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butylamino)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((4-methyl-1H-pyrazol-1-yl)methyl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-hydroxycyclopentyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-methoxycyclopentyl)-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((R)-1-(2H-tetrazol-2-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-cyanoethyl)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-((S)-1-(1H-tetrazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-Amino-1-oxopropan-2-yl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(isoxazol-4-yl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-Acetylaminoethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-5-(methylthio)-7-(prop-1-en-2-yl)-1H-indazol-4-yl) ) imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((S)-1,1,1-trifluoropropan-2-yl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((R)-1,1,1-trifluoropropan-2-yl)-1H-indazol-4-yl ) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((cyclopropylmethyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((R)-1-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((S)-1-methoxypropan-2-yl)-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1,2,2,2-tetrafluoroethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(furan-3-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1R,2R)-N-(6-(5-Chloro-7-(cyclopropyl(methyl)amino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-(methylthio)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(prop-1-en-2-yl)-5-(trifluoromethyl)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(prop-2-yn-1-ylamino)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-((1,1-difluoropropan-2-yl)amino)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-propionamidoethyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-carboxamidoethyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbut-1-en-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbut-2-en-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(1-(1H-imidazol-1-yl)ethyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(sec-butyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyrazine-2 -yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,4-dioxan-2-yl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(4-methyl-1H-imidazol-1-yl)ethyl)-1H-indazole-4- yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(7-(acetylamino(cyano)methyl)-5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a ]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(methylsulfonamido)ethyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1,1-difluoroprop-1-en-2-yl)-6-fluoro-1H-indazol-4-yl)imidazole [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbutan-2-yl)-1H-indazol-4-yl)imidazo[1,2 -a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(3-methylbut-2-en-2-yl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(1-(5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a]pyrazine- 6-yl)-1H-indazol-7-yl)ethyl)cyclobutanecarboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(2-fluorocyclopropyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine oxazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-Fluoro-7-(isopropylamino)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyrazin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(tetrahydrofuran-3-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyrazine -2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(2,2,2-trifluoroacetamido)ethyl)-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((methylthio)methyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-(1-(methylthio)ethyl)-1H-indazol-4-yl)imidazo[1,2- a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(1-(2,2-difluoroacetamido)ethyl)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(2,2,2-trifluoroacetamido)methyl)-6-fluoro-1H-indazol-4-yl) imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-((5-Chloro-6-fluoro-4-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)imidazo[1,2-a ]pyrazin-6-yl)-1H-indazol-7-yl)(cyano)methyl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(cyclopropionamido)methyl)-6-fluoro-1H-indazol-4-yl)imidazo[1, 2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-Chloro-7-(cyano(2,2-difluoroacetamido)methyl)-6-fluoro-1H-indazol-4-yl)imidazo [1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide; and (1S,2S)-N-(6-(5-Chloro-6-fluoro-7-((propan-2-yl-1,1,1,3,3,3-d6)amino)-1H-indium oxazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorocyclopropane-1-carboxamide. 25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1 or a pharmaceutically acceptable salt thereof. 26. A method of treating a subject suffering from a disease or condition associated with HPK1 modulation, the method comprising: A therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. 27. The method of claim 26, wherein the disease is cancer, wherein the compound of claim 1 is administered with an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA4 agent. 28. The method of claim 26, wherein the disease is cancer, metastasis, inflammation, or an autoimmune disease. 29. The method of claim 28, wherein the cancer is selected from the group consisting of epithelial cancer, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including but not limited to bladder cancer, brain tumor, breast cancer , cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular cancer, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer and thyroid cancer, acute lymphoblastic leukemia, acute myeloid cancer leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rhabdoid carcinoma, and Wilms tumor (Wilm's tumor).